Natural Product-Inspired Dopamine Receptor Ligands

Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson’s disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise. As this perspective will highlight, dopamine receptor targeting natural products play a pivotal role as scaffolds with unique and beneficial pharmacological properties, allowing for natural product-inspired drug design and lead optimization. As such, dopamine receptor targeting natural products still have untapped potential to aid in the treatment of disorders and diseases related to central nervous system (CNS) and peripheral nervous system (PNS) dysfunction.


INTRODUCTION
Isolated from natural sources as byproducts of primary or secondary metabolism, natural products are important conduits in drug discovery as lead compounds. 1The significance of natural products in pharmaceuticals cannot be overstated as over 30% of all FDA-approved new molecular entities (NMEs) are derived directly or inspired from microbial and plant species. 2 Optimized by natural selection pressures, natural products are refined to have optimal interactions with biological macromolecules, membrane permeability, biomolecular compatibility, and stability, thus sharing key properties of drug likeness. 3,4A recent analysis revealed that over 80% of CNS agents are derived directly or inspired from natural products, and the scaffolds of just 20 natural products yielded more than 400 clinically approved CNS drugs. 5haracteristically defined by their seven transmembrane domains, G protein-coupled receptors (GPCRs) are a superfamily of evolutionarily related integral membrane proteins.GPCRs are canonically coupled to heterotrimeric G proteins, consisting of three associated protein subunits (α, β, and γ).Activation of GPCRs results in the dissociation of the heterotrimeric G proteins into α-subunit and βγ-complex, further transducing the signal to stimulate the effector systems (which are dependent on the specific type of G protein).It should be noted that other signaling mechanisms (e.g., involving ion channels, receptor tyrosine kinases, or β-arrestins) are now known to exist.GPCRs are a critical drug target due to their implication in a wide range of diseases (including cancers, inflammatory diseases, mental disorders, metabolic disorders, cardiovascular diseases, and sensory disorders).In fact, over 30% of FDA-approved drugs target GPCRs. 6pamine receptors are GPCRs that recognize the endogenous, catecholamine dopamine (1, Figure 1).−9 It should be noted that two splice variants of the D 2 R occur (D 2short R or D 2S R and D 2long R or D 2L R), where D 2L R has a 29-mer peptide insertion in the third intracellular loop.These splice variants are predominantly localized to pre-and postsynaptic membranes, respectively. 10n addition to canonical signaling via G proteins, dopamine receptors are also known to signal via β-arrestin-based pathways.−15 Functional selectivity broadens the conventional definitions of pharmacol-ogy to expand the possibility of ligands to act with a mixture of classic characteristics (agonist, antagonist, and/or inverse agonist) depending on the effector pathway. 16,17−25 As the physiological functions of dopamine are quite extensive (including functions such as reward, sleep regulation, voluntary movement, penile erection, sympathetic regulation, cognitive function, olfaction, and hormonal regulation), dopamine receptors are attractive drug targets. 26

Journal of Medicinal Chemistry
At this time, no selective D 1 R agonist has been commercialized as a CNS-marketed drug.Traditional D 1 R agonists, such as A-86929 (2, Figure 2), dihydrexidine (3), and dinapsoline (4), are characterized by a catechol moiety as typified by dopamine.These ligands have poor CNS penetration and oral bioavailability due to the polarity of the catechol moiety. 27,28−31 Fenoldopam's mechanism of action relies on the activation of peripheral D 1-like receptors (no blood− brain barrier (BBB) permeability), which results in the reduction of systemic arterial blood pressure through renal vasodilation. 32he high degree of structural homology between the ligand binding site of D 1 R and D 5 R further exacerbates the difficulties in obtaining selective D 1 R ligands.This may be of therapeutic relevance since D 5 R is associated with cardiovascular side effects. 33Nevertheless, D 1 R is an important target for the treatment of cognitive deficits, particularly those associated with schizophrenia (which are not currently addressed by antipsychotic medications) and Parkinson's disease.−36 Relatively recently, researchers at Pfizer identified a new class of potent noncatechol D 1-like orthosteric agonists through a highthroughput screening (HTS) campaign of approximately 3 million compounds and subsequent structure−activity relationship (SAR) studies. 37,38The clinical efficacity of these agonists are still being evaluated with the optimized drug candidate, Tavapadon (6, K i D 1 R = 8.54 nM), currently under phase 3 clinical trials for Parkinson's disease in the United States (under development by Cerevel Therapeutics) [NCT04201093, NCT04223193]. 39,401 antagonism may also hold therapeutic promise as well, as exemplified by Ecopipam (SCH 39166, 7).Ecopipam, a more conformationally restricted benzazepine analog of SCH 23390 (8, the most used D 1 R reference antagonist), is a selective D l -like dopamine receptor antagonist (in vitro and in vivo) (K i at D 1 R of 1.2 nM, K i at D 5 R of 2 nM) with improved selectivity over 5-HT 2 and duration of action. 41Ecopipam displays a poor pharmacokinetic profile with extensive N-dealkylation of the Nmethyl group and O-glucuronidation of the phenol as well as low oral bioavailability (0.6%). 42,43Ecopipam was initially studied as a treatment for schizophrenia, but it displayed no efficacy (with reported side effects of anxiety, restlessness, sedation, and vomiting). 44,45Clinical studies for cocaine addiction revealed that while Ecopipam is an effective antagonist of the acute euphoric effects of cocaine, repeated administration failed to attenuate the subjective effects of cocaine. 46,47Clinical studies also revealed that Ecopipam is an effective obesity treatment; however, undesirable side effects (depression and reversible anxiety) halted its development as an antiobesity drug. 48,49copipam is currently under phase 3 clinical trials for Tourette's syndrome in the United States [NCT06021522, NCT05615220]. 50,51s one of the most established therapeutic targets for endocrine and neuropsychiatric disorders, the D 2-like family of dopamine receptors are promising therapeutic targets.Despite their importance, most investigational and clinically approved drugs are not subtype selective but rather are generally subfamily selective for all three D 2 -like receptors (D 2 R, D 3 R, and D 4 R) due to the high degree of similarity between the transmembrane (TM) regions. 52−57 Due to the prevalence of dopamine D 2-like signaling in the periphery (mainly in the pancreatic αand β-cells), D 2-like ligands often display metabolic dysfunction (e.g., systemic insulin resistance and dysglycemia). 58Moreover, side effects can result from antagonism of D 2 R signaling in the nigrostriatal system, causing extrapyramidal motor symptoms, and in the tuberoinfundibular pathway, resulting in elevated prolactin levels. 9,59evertheless, subtype-selective ligands for each D 2-like subtype (representative examples shown, 13−20, in Figure 4) are proven to have significant therapeutic applications.All FDA-approved antipsychotics are D 2 R partial agonists or antagonists.In addition, D 2 R ligands are used in the treatment of restless legs syndrome, postoperative nausea and vomiting, hyperprolactinemia, and Tourette's syndrome.D 3 R ligands are implicated in neurological disorders and are being investigated as potential treatments for substance use disorders. 60,61D 4 R agonists are proposed therapeutic agents for attention deficit hyperactivity disorder (ADHD) and sexual dysfunction, while D 4 R antagonists are candidates for the treatment of neuropsychiatric disorders. 62,63espite their clinical use, conventional dopamine receptor targeting drugs have debilitating side effects mainly due to suboptimal pharmacokinetic and pharmacodynamic properties.The identification of new chemotypes for dopamine receptor ligand discovery and the refinement of existing chemotypes are avenues that may lead to novel and pharmacologically advanced therapeutics.Natural products such as L-DOPA, benzyltetrahydroisoquinolines, aporphine alkaloids, tetrahydroprotoberberines, and ergolines have inspired and will continue to stimulate dopamine receptor ligand discovery efforts in that regard.Herein, we provide an informed perspective on the status of the aforementioned structural classes as a source of ligands for dopamine receptors.

DOPAMINE AND L-DOPA
−67 While dopamine cannot be used as a CNS drug, as it cannot cross the protective BBB, it can still be used as a peripheral vasostimulant for the treatment of low heart rate, cardiac arrest, and low blood pressure. 68,69Originally believed to be a biologically inactive amino acid, L-3,4-dihydroxyphenylalanine (L-DOPA, 21, Figure 5) was isolated from seedlings of Vicia faba beans in 1913. 70,71  DOPA is transported across the BBB by the large neutral amino acid transporter (LAT1) and is subsequently decarboxylated to dopamine by the endogenous enzyme aromatic L-amino acid decarboxylase.L-DOPA bypasses the rate-limiting step in dopamine synthesis (involving the enzyme tyrosine hydroxylase) and is more quickly converted to dopamine than the biosynthetic starting material for dopamine production, the amino acids L-tyrosine or L-phenylalanine.As such, L-DOPA is able to increase dopamine concentrations and reduce the motoric symptoms of Parkinson's disease.72 Parkinson's disease is a long-term CNS degenerative disorder, characterized by the idiopathic loss of dopamine neurons in the caudate-putamen.73 The loss of these neurons causes the manifestation of Parkinson's disease motor symptoms, characterized by rigidity, slowed movements, difficulty with walking, and tremors.
Most patients treated with L-DOPA will eventually develop L-DOPA-induced dyskinesia and motor fluctuations due to dysfunction in dopaminergic pathways. 72Particularly, dyskinesia is believed to be caused by pathological alterations in the nigrostriatal pathway. 74It should be noted that L-DOPA will increase dopamine concentration not just in the CNS but also in the peripheral nervous system (yielding undesirable side effects).As such, it is a standard clinical practice to coadminister a peripheral DOPA decarboxylase inhibitor (DDCI) (e.g., carbidopa, 22) with L-DOPA to prevent the conversion of L-DOPA to dopamine in the periphery. 75But, even with the coadministration of carbidopa, levodopa still has a relatively short half-life in plasma. 76Moreover, gastric motility is typically impaired as Parkinson's disease progresses, rendering the absorption of oral tablets of levodopa to be unpredictable due to erratic gastric emptying (levodopa is only absorbed in the superior part of the duodenum, the first part of the small intestine).Duopa (AbbVie), a gel formulation of levodopa and carbidopa, allows for the prevention of the peaks and troughs associated with traditional levodopa and carbidopa tablet therapy through continuous dosing of levodopa and carbidopa via a jejunal tube (requiring surgery at the beginning of the therapy). 77As an alternative, phosphonate prodrugs of levodopa (foslevodopa, 23) and carbidopa (foscarbidopa, 24) enable a more effective subcutaneous delivery with significant improvement of aqueous solubility at physiological pH (7.4). 78,79-[ 18 F]Fluoro-L-DOPA (FDOPA, 25) is a radiolabeled analog of L-DOPA, used in positron emission tomography (PET) imaging of dopaminergic nerve terminals in the striatum in patients with suspected Parkinsonian syndromes. 80
Synthetic BTHIQ derivatives bearing a cyclopentane motif and a phenyl substituent display high selectivity and affinity toward D 2-like receptors as exemplified by 35, affinity values (K i ) of 13 nM at D 1-like receptors and 13 000 nM at D 2-like receptors (K i D 1 /D 2 = 1000). 92is-benzyltetrahydroisoquinolines (BBTHIQs) are biosynthetically generated by dimerization of trioxygenated benzyltetrahydroisoquinolines via intermolecular oxidative coupling of (S)-and/or (R)-coclaurine and/or its N-methyl derivatives. 84BTHIQs with one diaryl ether bridge display higher dopaminergic activity (compared to BBTHIQs with two diaryl ether bridges with one diaryl ether bridge and one biphenyl bridge, or seco derivatives) as exemplified by (1R,1′S)thaligrisine (36) with IC 50 values based on the displacement of tritiated raclopride (D 2 -like receptors) and SCH23390 (D 1like receptors) of 27 and 5600 nM, respectively.93 Aporphine Alkaloids.Comprising one of the largest groups of natural isoquinolines, aporphine alkaloids are widely distributed in flowering plant families, (e.g., Annonaceae, Aristolochiaceae, Berberidaceae, Canellaceae, Eupomatiaceae, Hernandiaceae, Lauraceae, Leguminosae, Magnoliaceae, Menispermaceae, Monimiaceae, Papaveraceae, Piperaceae, Ranunculaceae, Rhamnaceae, Saururaceae, and Symplocaceae families).94−97 The tetracyclic backbone of naturally occurring aporphine alkaloids is typically decorated with substituents such as hydroxyl, methoxy, and methylenedioxy groups on the two aromatic rings.The aporphine alkaloids are a privileged scaffold in drug discovery, as natural aporphine alkaloids are reported to have a myriad of pharmacological activities including anti-  oxidant, antitumor, anticonvulsant, antiplasmodial, antiparkinsonian, antimalarial, antiprotozoal, and cytotoxic effects.15 The acid-catalyzed decomposition of morphine (37, Figure 9) led to the discovery of the nonselective dopamine receptor partial agonist, apomorphine (38) with the affinity trend of D 4 R 98−100 Apomorphine is also an antagonist at serotonin receptors (K i 5-HT 2A = 120 nM, K i 5-HT 2B = 132 nM, K i 5-HT 2C = 102 nM) and α-adrenergic receptors (K i α 1D = 64.6 nM, K i α 2A = 141 nM, K i α 2B = 66.1 nM, K i α 2C = 36.3nM).98−100 Apomorphine was initially explored as an experimental therapeutic for various conditions such as alcoholism, opioid addiction, erectile dysfunction, schizophre-nia, and coughing.101,102 It is now FDA approved (marketed under the name Apokyn) for the treatment of acute intermittent hypomobility�off episodes with late-stage Parkinson's disease patients treated with L-DOPA.103 By virtue of the ortho-catechol ring and phenethylamine moiety, apomorphine shares structural similarity to dopamine (a fundamental rationale for its affinity to dopamine receptors).104,105 Due to almost complete first-pass hepatic metabolism (via catechol-O-methylation, sulfation, and glucuronidation), apomorphine has very limited oral bioavailability (<4%) and has a short duration of action.106 However, apomorphine has the ability to cross the blood−brain barrier freely due to its lipophilic tetracyclic structure. Inact, apomorphine appears to concentrate in the brain, with a brainto-blood concentration ratio of 8:1.107 Apomorphine has undergone extensive SAR studies in efforts to optimize its selectivity, potency, and pharmacokinetic profile.The biphenyl unit, 11-hydroxy substitution, N-alkylation, and C-6α (R) configuration of aporphines are recognized as essential for dopaminergic activities.94,95,108 N-n-Propyl substitution improves D 2 R activity, whereas an N-methyl substituent improves D 1 R activity.109,110 This propyl effect of improving D 2 R activity can be applied to other dopaminergic molecules.111 The presence of a catechol group at the 1,2 position of the aporphine scaffold also favors dopamine receptor affinity, as exemplified by 1,2-demethylnuciferine (39).90 Despite 1,2demethylnuciferine displaying submicromolar affinity with the trend of D agonist through cAMP signaling with an EC 50 value of 10.2 μM (E max = 50.7%at 10 μM, E max = 92.7% at 100 μM) quantified using the HTRFbased cAMP kit in CHO-K1 cells stably expressing the cloned human D 2S R.
A series of N-substituted 11-hydroxynoraporphines and their esters of varying chain lengths was synthesized from morphine and evaluated for binding affinities at dopamine receptor sites in rat caudate-putamen membranes. 112From the series, the N-npropyl compound 40 (11-OH-NPa) exhibited the highest selectivity and affinity at D 2 R (K i D 1 R = 699 nM, K i D 2 R = 28.5 nM); however, its D 2 R affinity is lower than that of its catechol precursor NPA (41, K i D 1 R = 733 nM, K i D 2 R = 9.9 nM).The valeryl ester of 11-OH-NPa, compound 42, displayed maximal behavioral potency (via motor activity in normal adult male rats) after systemic injection, whereas the acetate ester of 11-OH-NPa (43) showed maximal behavioral potency (via motor activity in normal adult male rats) after enteric (intragastric) administration.Similarly, a series of N-alkyl-2-methoxy-11-hydroxynoraporphines was synthesized from thebaine (44) and evaluated for binding affinities at dopamine receptors in rat forebrain tissue. 113The most selective 11-monohydroxy aporphine was MCL-509 (45) (K i D 1 = 1,690 nM, K i D 2 = 44 nM), an orally active Parkinson's disease drug candidate. 114 2 receptors exist in two states, either as a functionally inert low-affinity state (D 2 low R) or as a functional high-affinity state (D 2 high R).115 The high-affinity and low-affinity receptors show a biphasic competition curve and have different binding affinities to various ligands.Evidence increasingly indicates that alterations in the density of D 2 receptors in the high-affinity state are more important to pathophysiological processes than alterations in the total receptor density.As such, the development of a selective D 2 R agonist that is capable of distinguishing between the high-and the low-affinity states is critical as a tool for diagnostics and therapeutics for psychosis and Parkinson's disease.115 Fluoroalkylation of a hydroxyaporphine substrate led to the development of MCL-536 (46; K i D 2 high R = 0.54 nM, K i D 2 low R = 490 nM) and MCL-538 (47; K i D 2 high R = 0.83 nM, K i D 2 low R = 750 nM) as novel D 2 high R-targeted probes for the dopaminergic system.116−118 Due to the high sequence identity (82% in transmembrane regions) between D 1 R and D 5 R, the development of subtypeselective D 1-like ligands is challenging and limited to only a few compounds.7,119−121 The development of ligands with D 1 R versus D 5 R selectivity (and vice versa) remains an area of significant interest in the field.In 2020, our group reported the synthesis and evaluation of two series of aporphine analogs bearing either a sole C-10 nitrogen substituent on the tetracyclic aporphine core or 1,2,10-trisubstituted aporphines (with both groups containing a nitro, aniline, or amide moiety at the C-10 position).122 All compounds except compound 48 lacked D 5 R affinity.The C-10 nitrogen monosubstituted analogs exhibited a preference for the serotonin 5-HT 1A R, while the 1,2,10trisubstituted analogs generally displayed dopamine receptor selectivity. Outof the two series of compounds, the 1,2,10trisubstituted aporphine 49 was identified as the ligand with the highest affinity toward D 1 R (K i = 58 nM) with low affinity toward 5-HT 2A R (K i = 1272 nM) and D 2 R (K i = 854 nM) and no affinity for the other receptors tested (5-HT 1A R and D 5 R).Compound 49 displays higher metabolic stability than apomorphine in human liver microsomes, which is not surprising as it lacks any common conjugation sites (amino, carboxy, hydroxy, or thiol groups) for phase II metabolism.Computational simulations revealed that the D 1 R versus D 5 R selectivity of 49 might arise from stronger hydrophobic contacts (primarily with phenylalanine residues) with D 1 R compared to D 5 R.
With the potential to bypass observed adverse effects, functional selectivity enables the activation of distinct subsequent signaling cascades or even the selective activation of a particular G protein subtype. 22,123As functional selectivity is still a relatively new paradigm in drug discovery, very few such studies have been performed on aporphines.A structure− functional−selectivity relationship (SFSR) study of the apomorphine scaffold revealed the structural motifs responsible for biased activity at both D 1-like and D 2-like receptors. 124It was found that alkyl and halogen substituents on the catechol ring generally do not contribute to functional selectivity; rather, these substituents reduce agonist activity at dopamine receptors for both β-arrestin 2 and G protein pathways.β-Arrestin-biased antagonism at both D 1 and D 2 receptors was observed with bromo substitution at either the C-1 ( 50 The natural aporphine, S-(+)-boldine (52, Figure 10), well known as a constituent of the bark and leaves of the Chilean tree Boldo (Peumus boldus Molina, Monimiaceae), 125−127 has served as a template for the construction of new aporphines.Boldo is used in folk medicine, primarily for the treatment of liver ailments.Although boldine is recognized as an effective antioxidant, it also displays antagonist activity at D 1-like and D 2-like receptors with IC 50 values of 400 and 520 nM, respectively, based on the displacement of [ 3 H]-SCH 23390 or [3H]-raclopride from their specific binding sites in rat striatum. 128Despite the affinity toward dopamine receptors, boldine does not display effective central dopamine antagonist activities in vivo as the high dose of 40 mg/kg boldine i.p. failed to produce any effect on striatal [ 3 H]raclopride binding in rat forebrain while [ 3 H]-SCH 23390 binding decreased by 25%.Furthermore, orally administered boldine is rapidly glucuronidated in the liver with a plasma elimination half-life of 31 min. 129Molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid was used to halogenate boldine to afford 3haloboldines and 3,8-dihaloboldines. 130Halogenation of boldine at C-3 favors affinity for rat brain D 1-like dopamine receptors compared to D 2-like dopamine receptors, as exemplified by 3-iodoboldine (53) with IC 50 values of 3 (D 1-like receptors) and 96 nM (D 2-like receptors) based on radioligand displacement studies in rat-brain membranes.
(S)-(+)-Glaucine ( 54) is a natural derivative of boldine, with no free hydroxyl group, and is used as an antitussive agent (mainly due to Ca 2+ channel antagonism).It is commercially isolated from the yellow horned poppy (Glaucium f lavum Crantz). 131Glaucine displays a lower affinity toward dopamine receptors than boldine, with IC 50 values of 3.90 (D 1-like receptors) and 3.02 μM (D 2-like receptors), measured by binding studies in rat-striatal membranes using [ 3 H]-SCH 23390 or [ 3 H]-raclopride. 128In vivo studies reveal some antidopaminergic properties of glaucine as the high dose of 40 mg/kg glaucine i.p. elicited a reduction of 50% for both [ 3 H]-SCH 23390 and [ 3 H]-raclopride binding in rat forebrain.Both boldine and glaucine inhibited penile erection, and apomorphine (0.1 mg/kg s.c.) induced yawning in rat models by over 50% at 40 mg/kg (i.p.) without impacting the metabolism of dopamine in rat and mouse forebrain tissues.Similar to boldine and glaucine, (S)-(+)-predicentrine (55) displays moderate activity at both D 1-like and D 2-like receptors with IC 50 values of 240 (D 1-like receptors) and 760 nM (D 2-like receptors) based on radioligand displacement studies in rat-striatal membranes. 1323-Halogenated and 3,8-dihalogenated derivatives of predicentrine had improved affinity for D 1-like receptors, as demonstrated by 3-bromopredicentrine (56; K i D 1-like = 15 nM, K i D 2-like = 613 nM) and 3iodopredicentrine (57; K i D 1-like = 6 nM, K i D 2-like = 831 nM). 132alogenated glaucine derivatives failed to exhibit any clear trend toward enhanced selectivity or any improvement with potency, indicating that the D 1-like enhanced potency with halogenation at C-3 is conditional with the presence of the 2-hydroxy group on the aporphine skeleton (and it is this moiety that predominantly determines the binding mode that favors D 1-like over D 2-like receptors).
As an isolate from the bark of the pukatea tree (Laurelia novaezelandiae), (R)-(−)-pukateine ( 58) is another aporphine congener with antioxidant and dopaminergic properties. 133he monohydroxyaporphine derivative displays IC 50 values of 400 (at D 1-like receptors) and 600 nM (at D 2-like receptors) based on radioligand binding experiments.Pukateine bears a meta hydroxyphenyl (at C-11) and 6aR configuration, both of which are associated with dopamine receptor activation. 94,134In 6hydroxydopamine unilaterally denervated rats, a dose of 8 mg/ kg but not 4 mg/kg of pukateine elicited a significant contralateral circling, which is a behavior classically associated with the actions of a dopamine agonist.Perfusion of pukateine (at 340 μM) through a microdialysis probe inserted into the striatum induced a significant increase in dopamine levels, indicating an agonist-like interaction with dopamine receptors.
Phenanthrene Alkaloids.While phenanthrene alkaloids do not contain a nitrogen heterocycle, they are considered alkaloids due to being biogenetically derived from aporphines (thus occurring in the same plant families as aporphines). 138he degradation of aporphines (for the most part) readily yields phenanthrene alkaloids.Hoffmann degradation is the classical (synthetic) method for the transformation of aporphines into phenanthrene alkaloids.The reaction involves the formation of a quaternary ammonium salt by treatment with an alkylating agent (usually methyl iodide or dimethyl sulfate) followed by anion exchange with silver oxide to form a quaternary ammonium hydroxide which can then be thermolyzed to the phenanthrene.3,4-Dihydroxy-and 3,4-methylenedioxyphenanthrenic derivatives (66 and 67, respectively, Figure 12) displayed high selectivity toward D 2-like receptors. 13966 displays affinity values (K i ) of 7700 nM at D 1-like receptors and 49 nM at D 2-like receptors (K i D 1 /D 2 = 157), whereas 67 displays affinity values of 6300 nM at D 1-like receptors and 66 nM at D 2-like receptors (K i D 1 /D 2 = 96).
Berberine and Tetrahydroprotoberberines (THPBs).The bright yellow compound berberine (68, Figure 13), a characteristic isolate of most barberries (Berberis plants), of the American goldenseal Hydrastis canadensis, and of the Chinese herb Coptis chinensis, is traditionally used as a textile dye and antiparasitic agent by many cultures in Eurasia and the Americas. 140,141Berberine displays a wide variety of pharmacological properties with implications for cancer, digestive diseases, neurological diseases, cardiovascular diseases, and metabolism disorders.Berberine is a weak dopamine D 1-like and D 2-like receptor antagonist (D 1 R IC 50 = 15.5 μM, D 2L R IC 50 = 17.1 μM, D 2S R IC 50 = 38.6 μM) (using HTRF assay for D 1 R and [ 35 S]GTPγS binding assay for D 2S R and D 2L R) and ameliorates the development of experimentally induced colitis in mice by suppressing innate and adaptive immune responses. 142sually isolated from Corydalis and Stephania species, tetrahydroprotoberberines (THPBs) have been found to display profound effects on the dopaminergic system. 143,144Several THPB natural products and their synthetic derivatives have been identified as dopamine receptor ligands with affinities and activities being primarily reported at D 1 R, D 2 R and (to a lesser extent) D 3 R.In THPB natural products, as in all of the biosynthetically related isoquinoline alkaloids, the aryl rings of the tetracyclic nucleus are usually substituted with hydroxyl or methoxyl groups in the two aryl rings.With a clear consensus, behavioral and biochemical evidence has illustrated that THPBs are antagonists at the D 2 family of dopamine receptors. 145The intrinsic activity of THPBs at the D 1 family of dopamine receptors is variable, with a majority of compounds being reported as antagonists and comparatively fewer as partial agonists.
Enantiomers of govadine exhibited drastically different behavioral and pharmacological properties. 146

nM). D-GOV and L-GOV exhibit modest affinity for adrenergic receptors [D-GOV (K
Rodent models predictive of antipsychotic efficacy and of positive symptoms of schizophrenia showed that L-GOV (but not D-GOV) had improved these measures.On the other hand, D-GOV (but not L-GOV) may be an effective cognitive enhancer, as it improved impairments in compromised memory function in delayed response tasks.
(S)-(−)-Tetrahydropalmatine (L-THP, 72) displays modest nanomolar to micromolar affinity and antagonist activity toward dopamine receptors with the order of D 1 R (K i = 124 nM) > D 2 R  (K i = 388 nM) ≫ D 3 R (K i = 1420 nM). 145,149The levo isomer of THP is responsible for the analgesic, sedative, and neuroleptic properties, whereas the dextro (R) isomer of THP has a distinct toxicologic action. 143,150-THP has been approved for use as an analgesic and sedative in China for over 50 years, originally isolated from Stephania rotunda, under the brand Rotundine or Rotundin.
−158 Substance use disorder is defined as a compulsive and habitual nonmedical self-administration of drugs despite having severe adverse consequences. 159Addictive drugs elevate extracellular levels of dopamine, rewiring the brain's dopaminergic  mechanisms. 160These alterations in the dopaminergic pathways result in decreased dopamine receptor expression in the brain, reducing interest in all activities but those that arise from habitual rewards.Due to the dopamine receptor polypharmacology of THPBs, these compounds have been proposed to be a novel source of pharmacotherapies for substance use disorders. 145,149−167 L-ICP was also shown to reduce behavioral sensitization and rewarding effects of cocaine in mice. 147−171 The clinical evidence for the efficacy of THPBs in substance use disorders is limited only to a single preliminary clinical trial conducted in China, examining the effects of L-THP on ameliorating heroin craving and increasing the abstinence rate in heroin users via a randomized, double-blinded, and placebocontrolled study of 120 heroin-dependent patients. 172The results suggest that L-THP has presumably therapeutic utility in the treatment of heroin addiction as the drug significantly ameliorated protracted abstinence withdrawal syndrome (PAWS).This pilot study does present several methodological limitations including not separating treatment seekers and nontreatment seekers (as they may have different responses to L- THP treatment), employing only pharmacotherapy without cognitive behavioral treatment (CBT), and utilizing only one low dose of L-THP with a short duration of 1 month to limit the risk of possible hepatic toxicity.Additional clinical evidence revealed that short-term L-THP administration does not exhibit significant differences in vital signs or side effects compared to the placebo group in cocaine users. 173HPBs can be semisynthetically prepared by the reduction of the relatively abundant protoberberines such as berberine, palmatine, and their partially O-demethylated analogs or synthetically prepared via Pictet−Spengler reaction, Bischler− Napieralski reaction, Pomeranz−Fritsch reaction, or Mannich reaction to construct the B-ring and C-ring in sequence. 174nitial studies on synthetic tetrahydroprotoberberines, focusing on 2,3,9-and 2,3,11-trisubstitution patterns, revealed several ligands with dopaminergic activity. 175The 2,3,9trihydroxy-THPB (74, Figure 14) exhibited the highest selectivity for the D 2-like receptors (K i D 1 /D 2 = 41) with affinity values (K i ) of 3800 nM at D 1-like receptors and 93 nM at D 2-like receptors.Replacement of the 3-OH with a chlorine atom on the A-ring (3-Cl-2,11-diOH, 75) resulted in increased affinity for D 1-like receptors (K i = 107 nM) but dramatically reduced the selectivity (D 2-like receptors, K i = 188 nM) (K i D 1 /D 2 = 0.6), which is in contrast to previous studies on BTHIQs where chlorination ortho to the oxygenated group in the A-ring resulted in increased affinity and selectivity toward D 2-like receptors. 85,176,177The presence of a methylenedioxy group in the 2,3 position (2,3-OCH 2 O-9-OH, 76) exerted lower selectivity for the D 2-like receptors (K i D 1 /D 2 = 10) with improved affinity for both dopamine types (D 1-like receptors, K i = 340 nM; D 2-like receptors, K i = 35 nM).
−180 Dual-acting ligands may be similar to bivalent ligands as they may also combine two pharmacophoric units linked by a spacer, except the spacer is shorter than those of bivalent ligands (with the aim not to simultaneously bind to both protomers but rather to simply deliver both pharmacophoric moieties simultaneously). 178,181Due to their inherent pharmacological properties, bivalent ligands tend to be better suited as pharmacological tools whereas dual-acting ligands may have further application as therapeutic agents. 179−185 This targeting strategy is based on the observation that coadministration of a D 1 R partial agonist (SKF 77434) and a D 3 R antagonist (NGB 2904) produced robust decreases in cocaine seeking and reward in rats.This indicates a synergistic effect between D 1 R agonism and D 3 R antagonism. 186ur initial efforts were focused on SAR studies with L-SPD as a lead molecule.2][183][184][185]187 Our structure−affinity relationship studies on L-SPD revealed that bromination at the C-12 position improved D 1 R affinity but generally diminished D 3 R affinity. Homologtion at the C-9 position improved D 1 R selectivity versus D 2 R and D 3 R (often lacking affinity at D 2 R), whereas alkylation of the C-10 phenolic group with up to 6 carbon atoms in length was tolerated for D 1 R affinity.Homologation at the C-3 position generally led to retention of the magnitude of D 3 R affinities with the notable exception of fluoroethylation, which resulted in an approximate 3-fold reduction in D 3 R affinity compared to L-SPD.
Only a handful of studies have been undertaken to examine the functional selectivity bias of THPBs.Data gathered to date by our group suggest that THPBs function as antagonists at both G protein and arrestin pathways (Figure 15) (cAMP functional assays, Promega's split luciferase-based GloSensor cAMP biosensor technology, or Lance Ultra cAMP IC50 assays; βarrestin assays, TANGO assays, or DiscoveRx PathHunter technology).L-SPD was found to be a potent pan-dopamine receptor antagonist of both G protein-and β-arrestin-mediated signaling (thus lacking functional selectivity), determined using DiscoveRx PathHunter technology. 151

ERGOLINES
−193 Embedded within the tetracyclic structure of the ergolines are the defining features of the monoamine neurotransmitters serotonin, noradrenaline, and dopamine, empowering ergolines to act as potent agonists, partial agonists, or antagonists at these receptors. 194Derivatives of ergolines are categorized into 3 main classes: lysergic acid and its simple amides, ergopeptines, and clavines. 195,196Lysergic acid derivatives contain a carboxylic acid group at position 17 with most lysergic acid derivatives being functionalized by an amide linkage to that position (e.g., ergine and ergonovine).The peptide ergot alkaloids are defined by a tripeptide-derived, cyclol-lactam structure attached as a C-17 amide substituent (e.g., ergocristine, ergotamine, and ergovaline).The clavine alkaloids are classified as the derivatives of 6,8dimethylergoline or the tricyclic precursors (i.e., agroclavine, elymoclavine, and festuclavine).
While naturally occurring ergolines generally lack selectivity between dopamine receptor subtypes and other biogenic amine receptors, a select number of semisynthetic ergolines display a preference toward dopamine receptors. 194Several ergolines are used as antiparkinsonian drugs [e.g., bromocriptine (81), lisuride (82), and pergolide (83), Figure 15] and inhibitors of prolactin release [e.g., 81−83 and cabergoline (84)] due to their agonist activity at dopamine receptors. 197,198The simulation of neostriatal D 1 and D 2 receptors is associated with the antiparkinsonian effect of ergolines, whereas the simulation of D 2 or D 4 receptors mediates the suppression of prolactin secretion from the anterior pituitary. 199,200eduction of the methyl ester of lysergic acid with lithium aluminum hydride yields lysergol (85), a key intermediate in the preparation of semisynthetic ergoline analogs. 201As the hydroxy group of lysergol could undergo nucleophilic substitution upon conversion to sulfonic ester (e.g., mesylate or tosylate), researchers at Lilly were able to introduce a methylthio moiety leading to pergolide. 202Zikań and Semonskýat the Research Institute for Pharmacy and Biochemistry at Prague (later SPOFA) developed lisuride via derivation of methysergide (86)  in efforts toward the development of an antimigraine agent. 203In 1954, Moses Shelesnyak recognized that ergotoxine (87) could inhibit deciduoma formation that was associated with ovum implantation in rats, attributable to inhibition of prolactin secretion. 201,204This led to researchers at Sandoz developing ergot analogs that selectively inhibited prolactin secretion, leading to the development of bromocriptine. 201,205istal substituents on an ergoline-derived scaffold by combining two privileged scaffolds, indole and phenylpiperazine (88−90), yielded potent D 2 R ligands with intrinsic activities ranging from full agonism to partial agonism. 206Alkylation on the nitrogen on the piperazine moiety led to a series of D 2 R agonists with a wide range of binding affinities with the most potent D 2L R ligand bearing an N-(1,1′-biphenyl-3-yl)methyl group (88) (K i = 0.65 nM, E max = 35%).An inverse relationship was observed between the size of the amine substituent and the D 2 R efficacy, where smaller alkyl substituents are full agonists (e.g., 89 and 90).Alkylation of the nitrogen on the indole moiety resulted in ligands with serotonin 5-HT 6 receptor affinity.
On both a functional and a molecular level, adenosine and dopamine receptors have interactions with each other as heteromeric complexes. 207Adenosine receptor-selective antagonists display antiparkinsonian activities and exhibit neuroprotective properties (rarely seen with currently used antiparkinsonian drugs).As such, combining adenosine A1 receptor (A 1 R) and A 2A R antagonism with dopamine D 1 R and D 2 R agonism into a single multivalent ligand could lead to novel treatments for Parkinson's disease with improved efficacy and safety. 208,209As ergot alkaloids are privileged structures with an inherent ability to interact with diverse biological receptors, a combinatorial approach based on the ergoline scaffold allowed the identification of compounds with dual adenosine antagonist and dopamine agonist activity as exemplified by 91 (A 1 R K D = 0.10 μM, D 2 high R K D = 2 μM). 210

MISCELLANEOUS DOPAMINE RECEPTOR-TARGETED NATURAL PRODUCTS
Cannabidiol (CBD, 92, Figure 16) is a phytocannabinoid found in the Cannabis sativa plant, accounting for up to 40% of the plant's extract. 211Compared to Δ 9 -tetrahydrocannabinol (Δ 9 -THC, 93), CBD lacks psychotomimetic and other psychotropic effects.Δ 9 -THC displayed binding affinity and functional CBD is FDA approved for the treatment of seizures associated with Lennox−Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in patients 1 year of age and older (under the brand name Epidiolex).CBD is implicated in other medical illnesses including anxiety, psychosis, and depression, although it is not FDA approved for these conditions. 211,213The clinical antipsychotic effects of CBD correlate with its partial agonist activity at D 2 high R (K i D 2 high R = 11 nM, K i D 2 low R = 2800 nM) in a similar biphasic manner as aripiprazole, a dopamine partial agonist antipsychotic drug. 214urarinone ( 94) is an abundant lavandulylated flavonoid isolated from the perennial shrub Sophora f lavescens (Fabaceae). 215Known as Kushen, the dried roots of S. f lavescens are used in traditional Chinese medicine for the treatment of cancer and inflammatory diseases. 216Kurarinone displays moderate to potent inhibitory activity on acetylcholinesterase (AChE, IC 50 = 74.28μM), beta-secretase 1 (BACE 1, IC 50 = 24.50μM), and butyrylcholinesterase (BChE, IC 50 = 5.29 μM) using either Ellman's colorimetric method (for AChE and BChE) or with BACE1 FRET assay kit (β-Secretase) kit. 217,218Functional HTRF-based cAMP assays (for D 1 R and D 4 R) and Ca 2+ flux assays (for D 2L R) revealed kurarinone exhibited an antagonist effect on D 1 R (IC 50 = 42.1 μM) and an agonist effect on D 2L R (EC 50 = 22.4 μM) and D 4 R (EC 50 = 71.3μM), suggesting its potential to alleviate various neurodegenerative diseases (NDDs). 215solated from the perennial herb Atractylodes macrocephala Koidz, atractylon (95) is a furan-containing compound with several pharmacological activities, including anticancer, antiviral, anti-inflammation, and gastroprotective properties. 219ecently, it was demonstrated that atractylon is a D 2 R agonist in a dose-dependent manner (using a piggyBac-TANGO assay) with an IC 50 of 2.5 μM. 220Atractylon attenuated motor deficits and abnormal gait disturbances as well as protected dopaminergic neurons in MPTP-induced PD mice, indicating potential as a therapeutic agent in the treatment of motor symptoms of Parkinson's disease.
Monoamine oxidase (MAO) is a mammalian flavoenzyme that catalyzes the inactivation pathway of several neurotransmitters (e.g., adrenaline, dopamine, norepinephrine, and serotonin) through oxidative deamination. 221In the biochemical process, oxidative damage can occur as hydrogen peroxide is the major and direct side product of MAO activity.Thus, inhibitors of MAO have neuroprotective properties. 222MAO exists in two isoforms, MAO-A and MAO-B, with different tissue distribution and substrate-inhibitor recognition sites.Bromophenols (96 and 97) from the red alga Symphyocladia latiuscula are good D 3 R/D 4 R agonists and are moderate MAO inhibitors and as such are implicated in the management of neurodegenerative diseases. 223 Luteolin (98) is another flavonoid, widely distributed in the plant kingdom (e.g., Artemisia montana, Cirsium japonicum, Cynara scolymus, and Taraxacum of f icinale). 224Luteolin exhibited selective inhibition of MAO-A [MAO-A (IC 50 = 8.57μM), MAO-B (IC 50 > 100 μM)] and is a selective antagonist of D 4 R (IC 50 = 39.6 μM) and vasopressin receptor 1A (V IA R) (IC 50 = 19.5 μM) calculated from a dose−response curve.

CONCLUSION AND PERSPECTIVES
Natural products are an invaluable resource as lead compounds in drug discovery, inspiring a countless number of drugs in the treatment of debilitating diseases and illnesses.Despite the prevailing notion highlighting the potential for dopamine receptor-targeted ligands as therapeutic agents for the treatment of numerous diseases and illnesses, currently available ligands have limited success due to inadequacy in selectivity and other pharmacological properties.Subtype-selective dopaminergic drugs are lacking in the market.
Among the natural product scaffolds described, aporphines, THPBs, and ergolines have received the most scientific attention in relation to their dopamine receptor targeting.However, the cularines and miscellaneous natural products described have been relatively underexplored in this regard.
The development of functionally selective dopamine receptor tools is an area where natural product templates can have a significant impact.The identification of β-arrestin-biased D 2 R antagonists from the aporphine scaffold makes for a promising outlook in that direction.
Compared to the one-target, one-disease paradigm, polypharmacology enables compounds to have enhanced efficacy and safety through synergetic interactions.There is clear evidence that some diseases with complex etiology and/or symptomatology may be remedied optimally by drugs with multiple pharmacological actions.As privileged dopamine receptor-targeted scaffolds, aporphines, THPBs, and ergolines, in particular, offer a unique entry point to develop ligands with multireceptor activities.
While significant progress has been made in the development of dopamine receptor agents, it is clear that further progress is needed as the pharmacological properties can still be improved upon.Dopamine receptor-targeted natural products still have untapped potential in the development of therapeutic and investigative agents, and it is anticipated that they will continue to form a nucleus of inspiration for synthetic studies and drug discovery.

Figure 1 .
Figure 1.Structure and dopamine receptor affinities and activities of dopamine.

Figure 2 .
Figure 2. Representative selective agonists and antagonists of D 1-like receptors.

Figure 4 .
Figure 4. Representative selective agonists and antagonists of D 2-like receptors.

Table 1 .
Characteristics of Dopamine Receptors