[Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor.]
J Pharmacol Sci. 2006 Oct;102(2):189-95. Epub 2006 Oct 7.
Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor.
Muntasir HA, Bhuiyan MA, Ishiguro M, Ozaki M, Nagatomo T.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Japan.
Mutations producing constitutively active G-protein coupled receptors have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT(2A) receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT(2A) receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT(2A)-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT(2A)-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT(2A) receptor, we demonstrated that like other 5-HT(2A)-receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate levels. However, there were no significant differences between sarpogrelate and other 5-HT(2A)-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT(2A) receptor may be a key component of the mechanism of action of sarpogrelate.<<
Not sure how relevant this is, given the MOA of this compound involves "stabilization of the inactive conformation of the 5-HT(2A) receptor," but maybe it points to possible off-target effects or side effects of a cardiovascular nature? Nothing of that nature has been disclosed about ACP-103, but the trials have been small so far. OTOH, I may be off base with any concern at all stemming from this, which is why I'm bringing to the attention of someone with a better background in the science.
And, bonus, this time it involves little chemistry, so I expect a prompt and authoritative reply, heh, heh, heh.
Cheers, Tuck |
