Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels.
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.
Patil
Shivaputra
S
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Bukiya
Anna N
AN
Li
Wei
W
Dopico
Alejandro M
AM
Miller
Duane
D
D000818:Animals; D006880:Hydroxy Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists*; D008095:Lithocholic Acid / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D032342:Muscle Cells / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats
D006880:Hydroxy Acids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008095:Lithocholic Acid