Inverse Agonist Activity of several 5-HT2A Receptor Antagonists at the Constitutively Active Human 5- HT2A receptor

INTRODUCTION: 5-HT2A receptors are of significant clinical interest because of their potential involvement in mediating a variety of physiological functions, including platelet aggregation, thrombus formation, coronary artery spasm, vascular smooth muscle contraction, appetite, sleep, cognition, perception, mood, and other central nervous system functions. Different antagonists such as ketanserin, ritanserin, cyproheptadine, and sarpogrelate have been found or suggested to have therapeutic potentials on these pathophysiological effects. Constitutively active mutant receptors have been a valuable tool to demonstrate that certain ligands stabilize inactive conformations. Those ligands are known as inverse agonists, given they have the opposite effect of agonists. Recently, several receptors have been shown to be constitutively active in vivo, implying that inverse agonists may have preferred therapeutic applications in the pathophysiology of several diseases. Because of the numerous physiological functions and pathological conditions involving the 5-HT2A receptor in the central nervous system and periphery, it is possible that activating mutations of the 5-HT2A receptor may be responsible for disease states. It has been reported that in the 5-HT2A receptor, the substitution of cysteine 322 of the third intracellular loop to lysine (C322K) can be rendered constitutively active (1). The purpose of the present study was to determine the inverse agonist activity of several 5-HT2A receptor antagonists, such as ritanserin, ketanserin, cyproheptadine, sarpogrelate and its active metabolite, M-1 at the constitutively active mutant (C322K) 5-HT2A receptor.