R-(−)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT1A receptor ligands

doi:10.1016/j.bmcl.2007.05.057

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 15, 1 August 2007, Pages 4128-4130

https://doi.org/10.1016/j.bmcl.2007.05.057 Get rights and content

Abstract

Several N-substituted-11-hydroxy-10-hydroxymethyl- and 11-hydroxy-10-methylaporphines were synthesized and their binding affinities at dopamine D₁ and D₂ receptors and serotonin 5-HT_1A and 5-HT_2A receptors in rat forebrain tissue were evaluated. Tested compounds displayed moderate to high affinity to 5-HT_1A receptors but low affinity to D₁ and D₂ receptors. The most potent novel 5-HT_1A agent was R-(−)-N-methyl-10-hydroxymethyl-11-hydroxyaporphine.

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Acknowledgments

This work was supported by the Branfman Family Foundation (to J. L. N. and R. J. B.), HD-052752 (to FIT), by the Bruce J. Anderson Foundation, and the McLean Private Donors Neuropsychopharmacology Research Fund (R. J. B.). Morphine and thebaine were generously supplied by Mallinkrodt Inc.

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Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT<inf>7A</inf>R ligands
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Aporphine alkaloids are known to have affinity across a range of serotonergic and dopaminergic receptors. In particular, structure-affinity relationship studies on aporphines have resulted in the identification of potent and selective ligands for serotonin 5-HT1AR13–16 and dopamine D2R17,18 as well as compounds with interesting multi-receptor profiles.19–22 In contrast to their evaluation as 5-HT1A receptor ligands, the evaluation of aporphines as 5-HT7R ligands has been little studied.
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Evaluation of structural effects on 5-HT<inf>2A</inf> receptor antagonism by aporphines: Identification of a new aporphine with 5-HT<inf>2A</inf> antagonist activity
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A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT_2A and α_1A adrenergic receptors.
With regards to 5-HT_2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT_2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT_2A antagonism.
Compound 12b was the most potent 5-HT_2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α_1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α_1A antagonism.
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(±)-Nantenine analogs as antagonists at human 5-HT<inf>2A</inf> receptors: C1 and flexible congeners
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The abundance of serotonin (5-HT) in the central nervous system can explain its role in the regulation of various functions, such as sleep, feeding, sexuality, emotional status, and pain. In addition, 5-HT localized in “cognitive pathways” with hippocampus and frontal cortex as the main target structures, is involved in learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors, differentially associated to cognitive mechanisms. Abundant data available reveals that the administration of 5-HT_2A/2C and 5-H_T4 receptor agonists, or 5-HT_1A, 5-HT₃ and 5-HT_1B antagonists improves memory and has a facilitatory effect on learning in situations involving a high cognitive demand. On the contrary 5-HT_2A/2C and 5-HT₄ receptors antagonists, or 5-HT_1A, 5-HT₃ and 5-HT_1B receptors agonists have opposite effects. Although these results are contradictory, or even opposite, it is important to take into account the effect of global, and unspecific, stimulation of serotonergic receptors and the activation of other neurotransmission systems, together with the type of task used, the way it is administered and the ligand affinity.
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2008, Bioorganic and Medicinal Chemistry
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R-(−)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT1A receptor ligands

Abstract

Graphical abstract

Section snippets

Acknowledgments

Eur. J. Pharmacol.

Eur. J. Pharm.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Chirality

R-(−)-N-alkyl-11-hydroxy-10-hydroxymethyl- and 10-methyl-aporphines as 5-HT_1A receptor ligands