Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels

doi:10.1016/j.bmcl.2008.03.080

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 11, 1 June 2008, Pages 3427-3430

https://doi.org/10.1016/j.bmcl.2008.03.080 Get rights and content

Abstract

Physiological and pharmacological agents that activate large conductance, voltage-, and calcium-gated potassium (BK) channels located in the smooth muscle are effective vasodilators. Thus, activators of smooth muscle BK channels may be potential therapeutic tools to treat cardiovascular disease associated with vasoconstriction and/or impaired dilation, such as cerebrovascular spasm and constriction. We previously showed that lithocholic acid (LC) and other cholane derivatives activated smooth muscle BK channels and, thus, caused endothelium-independent cerebral artery dilation. However, clinical use of these cholane derivatives could be limited by the actions of these steroids, such as elevation of intracellular calcium and induction of apoptosis. Using LC as template, we designed and synthesized a series of hydroxy-alkynoic acids and corresponding methyl esters, as putative, non-steroid BK channel activators. Indeed, the newly synthesized compounds effectively and reversibly activated rat cerebrovascular myocyte BK channel at concentrations similar to those found effective with LC. Among all the novel compounds tested, C-10 hydroxy-alkynoic acid methyl ester appears to be the most effective activator of vascular myocyte BK channels.

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Acknowledgment

This work was supported by the NIH Grants HL77424 (A.M.D.).

References and notes (17)

T. Maruyama et al.
Biochem. Biophys. Res. Commun.
(2002)
J.V. Gerasimenko et al.
J. Biol. Chem.
(2006)
S. Modica et al.
FEBS Lett.
(2006)
P. Orio et al.
News Physiol. Sci.
(2002)
J.E. Brayden et al.
Science
(1992)
J.H. Jaggar et al.
Acta Physiol. Scand.
(1998)
A.M. Dopico et al.
J. Gen. Physiol.
(2002)
A.N. Bukiya et al.
Mol. Pharmacol.
(2007)

There are more references available in the full text version of this article.

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Discovery of agonist–antagonist pairs for the modulation of Ca [2]+ and voltage-gated K+ channels of large conductance that contain beta1 subunits
2022, Bioorganic and Medicinal Chemistry
Citation Excerpt :
First, the endogenous agents that interact with BK beta1 also interact with a myriad of receptors that mediate major physiological/pharmacological systemic effects, such as estrogen, farnesoid and leukotriene receptors 21–23. Second, the exogenous agents identified so far, and most endogenous agents, activate BK at tens of μM; concentrations well above those required to interact with receptors other than BK 14–15,18–19,24–25. Thus, none of these compounds received approval for therapeutic use as SM relaxants/vasodilators.
Large conductance, calcium/voltage-gated potassium channels (BK) regulate critical body processes, including neuronal, secretory and smooth muscle (SM) function. While BK-forming alpha subunits are ubiquitous, accessory beta1 subunits are highly expressed in SM. This makes beta1 an attractive target for pharmaceutical development to treat SM disorders, such as hypertension or cerebrovascular spasm. Compounds activating BK via beta1 have been identified, yet they exhibit low potency and off-target effects while antagonists that limit agonist activity via beta 1 remain unexplored. Beta1-dependent BK ligand-based pharmacophore modeling and ZINC database searches identified 15 commercially available hits. Concentration-response curves on BK alpha + beta1 subunit-mediated currents were obtained in CHO cells. One potent (EC₅₀ = 20 nM) and highly efficacious activator (maximal activation = ×10.3 of control) was identified along with a potent antagonist (K_B = 3.02 nM), both of which were dependent on beta1. Our study provides the first proof-of-principle that an agonist/antagonist pair can be used to control beta1-containing BK activity.
Regulation of Ca2 +-Sensitive K+ Channels by Cholesterol and Bile Acids via Distinct Channel Subunits and Sites
2017, Current Topics in Membranes
Citation Excerpt :
Recognition of the latter ligand by the LCA site renders both BK channel activation and endothelium independent, artery dilation (Bukiya et al., 2013). Because (1) BK β1 is abundant in all types of smooth muscle and highly conserved among species, (2) the LCA site was identified using rat and human β1, the BK β1 LCA-sensing site represents an attractive target for nonsteroidal, LCA-structural analogs (Bukiya, Patil, Li, Miller, & Dopico, 2012; Bukiya et al., 2013; McMillan et al., 2014; Patil, Bukiya, Li, Dopico, & Miller, 2008) that could serve not only as vasodilators but also to counteract SM enhanced contraction in nonvascular tissues, as found in asthma, erectile, bladder, and uterine dysfunction. As described above, CLR and LCA molecules share a considerable number of chemical features: an amphiphilic character (albeit CLR is much more hydrophobic than hydrophobic BA such as LCA); the presence of a hydroxyl group at C3 (albeit in β and α configuration in CLR and natural BA, respectively), the large hydrophobic steroidal nucleus (cholestane and cholane for CLR and BAs), and a freely movable lateral chain at C17 (much more hydrophobic in CLR).
Cholesterol (CLR) conversion into bile acids (BAs) in the liver constitutes the major pathway for CLR elimination from the body. Moreover, these steroids regulate each other's metabolism. While the roles of CLR and BAs in regulating metabolism and tissue function are well known, research of the last two decades revealed the existence of specific protein receptors for CLR or BAs in tissues with minor contribution to lipid metabolism, raising the possibility that these lipids serve as signaling molecules throughout the body. Among other lipids, CLR and BAs regulate ionic current mediated by the activity of voltage- and Ca^2 +-gated, K⁺ channels of large conductance (BK channels) and, thus, modulate cell physiology and participate in tissue pathophysiology. Initial work attributed modification of BK channel function by CLR or BAs to the capability of these steroids to directly interact with bilayer lipids and thus alter the physicochemical properties of the bilayer with eventual modification of BK channel function. Based on our own work and that of others, we now review evidence that supports direct interactions between CLR or BA and specific BK protein subunits, and the consequence of such interactions on channel activity and organ function, with a particular emphasis on arterial smooth muscle. For each steroid type, we will also briefly discuss several mechanisms that may underlie modification of channel steady-state activity. Finally, we will present novel computational data that provide a chemical basis for differential recognition of CLR vs lithocholic acid by distinct BK channel subunits and recognition sites.
Multi-generational pharmacophore modeling for ligands to the cholane steroid-recognition site in the β<inf>1</inf> modulatory subunit of the BK<inf>Ca</inf> channel
2014, Journal of Molecular Graphics and Modelling
Large conductance, voltage- and Ca²⁺-gated K⁺ (BK_Ca) channels play a critical role in smooth muscle contractility and thus represent an emerging therapeutic target for drug development to treat vascular disease, gastrointestinal, bladder and uterine disorders. Several compounds are known to target the ubiquitously expressed BK_Ca channel-forming α subunit. In contrast, just a few are known to target the BK_Ca modulatory β₁ subunit, which is highly expressed in smooth muscle and scarce in most other tissues. Lack of available high-resolution structural data makes structure-based pharmacophore modeling of β₁ subunit-dependent BK_Ca channel activators a major challenge. Following recent discoveries of novel BK_Ca channel activators that act via β₁ subunit recognition, we performed ligand-based pharmacophore modeling that led to the successful creation and fine-tuning of a pharmacophore over several generations. Initial models were developed using physiologically active cholane steroids (bile acids) as template. However, as more compounds that act on BK_Ca β₁ have been discovered, our model has been refined to improve accuracy. Database searching with our best-performing model has uncovered several novel compounds as candidate BK_Ca β₁ subunit ligands. Eight of the identified compounds were experimentally screened and two proved to be activators of recombinant BK_Ca β₁ complexes. One of these activators, sobetirome, differs substantially in structure from any previously reported activator.
Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype
2018, PLoS ONE
Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat
2017, Pflugers Archiv European Journal of Physiology
Lipid regulation of BK channel function
2014, Frontiers in Physiology

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^†: These authors contribute to the paper equally.

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Bioorganic & Medicinal Chemistry Letters

Abstract

Graphical abstract

Section snippets

Acknowledgment

References and notes (17)

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

FEBS Lett.

News Physiol. Sci.

Science

Acta Physiol. Scand.

J. Gen. Physiol.

Mol. Pharmacol.

Cited by (9)

Discovery of agonist–antagonist pairs for the modulation of Ca <sup>[2]+</sup> and voltage-gated K<sup>+</sup> channels of large conductance that contain beta1 subunits

Regulation of Ca<sup>2 +</sup>-Sensitive K<sup>+</sup> Channels by Cholesterol and Bile Acids via Distinct Channel Subunits and Sites

Multi-generational pharmacophore modeling for ligands to the cholane steroid-recognition site in the β<inf>1</inf> modulatory subunit of the BK<inf>Ca</inf> channel

Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype

Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat

Lipid regulation of BK channel function