A Novel 5-HT&lt;sub&gt;2&lt;/sub&gt; Antagonist, Sarpogrelate Hydrochloride, Shows Inhibitory Effects on Both Contraction and Relaxation Mediated by 5-HT Receptor Subtypes in Porcine Coronary Arteries

Japanese Journal of Pharmacology

Watanabe

Nakazawa

et al. 2001

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ABSTRACT-This study investigated the binding affinities of a newly synthesized 5-HT2 antagonist, AT-1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate) for [3 H]ketanserin bindings to 5-HT2 receptors in the rabbit cerebral cortex membranes using the radioligand binding assay method. The affinity of this compound was also compared with other 5-HT2-selective antagonists such as ketanserin, sarpogrelate, cyproheptadine and ritanserin, and the results showed that AT-1015 has a high pKi value for the 5-HT2 receptor. The rank order of these antagonists are: ritanserin > ketanserin @ AT-1015 > cyproheptadine @ sarpogrelate. We also evaluated the dissociation ability (slow or rapid) of AT-1015 in the rabbit cerebral cortex membrane and compared it with other 5-HT2 antagonists using the radioligand binding assay method. The blockade of [3 H]ketanserin binding sites in the rabbit cerebral cortex induced by ketanserin and sarpogrelate was readily reversed by washing, whereas the inhibition by AT-1015, cyproheptadine and ritanserin was not readily reversed by washing. The % of control after washing are 76.10% and 49.55% for AT-1015 at 10 -7.5 and 10 -7.0 M, 67.32% and 50.17% for cyproheptadine at 10 -7.5 and 10 -7.0 M, and 72.38% and 39.80% for ritanserin at 10 -9.5 and 10 -9.0 M concentrations, respectively. Thus, these findings suggest that AT-1015 has antagonistic properties towards the 5-HT2 receptor and also shows that AT-1015 slowly dissociates from the 5-HT2 receptor, whereas, ketanserin and sarpogrelate dissociate rapidly from the 5-HT2 receptor, which do not correlate with their affinity.Keywords: AT-1015, 5-HT2-receptor antagonist, Cerebral cortex (rabbit) Through its interactions with different receptor subtypes in the central and peripheral nervous system, 5-hydroxytryptamine (5-HT), a neurotransmitter, has diverse physiological functions (1). These diverse responses are elicited through the activation of a large family of 5-HT-receptor subtypes. So far, more than 14 kinds of 5-HT-receptor subtypes have been confirmed (2). Ketanserin, the first selective [3 H]-ligand for labelling the 5-HT2 receptors, contributed to further investigations to determine the localization of 5-HT2 receptors in the central nervous system and peripheral tissues (3). 5-HT2 receptors are demonstrated on both platelet membranes and brains by radioligand binding assay methods (4 -6).Previously we (7) reported that AT-1015-piperidinecarboxamide monohydrochloride monohydrate) was a strong noncompetitive 5-HT2 antagonist, comparing it with ketanserin, and it inhibited the contraction response of porcine coronary arteries induced by 5-HT and a-methylserotonin. Kihara et al. (8) also reported that AT-1015, which is newly synthesized as a 5-HT2 antagonist, blocked vascular and platelet 5-HT2A receptors and prevented laurate-induced peripheral vascular lesion in rats. The activity of AT-1015 on selective inhibition of 5-HT2A-mediated platelet aggregation was almos...

Section: Discussionsupporting

confidence: 80%

Assessment of Affinity and Dissociation Ability of a Newly Synthesized 5-HT2 Antagonist, AT-1015: Comparison With Other 5-HT2 Antagonists

Japanese Journal of Pharmacology

Watanabe

Nakazawa

et al. 2001

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“…5) It inhibits thrombus formation, 6,7) lowers platelet aggregation, 8,9) inhibits both serotonin-induced coronary artery spasm, 10) and contraction 11) in porcine model as well as vascular smooth muscle cell proliferation. 12) Presently these pathophysiological effects are claimed to be mediated by 5-HT 2A receptors.…”

mentioning

confidence: 99%

Site-Directed Mutagenesis of the Serotonin 5-Hydroxytryptamine2C Receptor: Identification of Amino Acids Responsible for Sarpogrelate Binding

Muntasir

Takahashi

Biological & Pharmaceutical Bulletin

et al. 2006

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“…All of these pathophysiological effects are mediated by the 5-HT2A subtype. Previously we reported that sarpogrelate inhibited the contraction response induced by 5-HT in pig coronary artery mediated by the 5-HT 2A subtype (19).…”

Section: Received January 28 2002 Accepted May 30 2002mentioning

confidence: 82%

“…Sarpogrelate inhibits thrombus formation (14,15) and suppresses platelet aggregation (16,17). It inhibits 5-HT induced coronary artery spasm (18) and contraction of coronary artery in the porcine model mediated by 5-HT and = -methylserotonin (19) and also inhibits vascular smooth muscle cell proliferation (20). All of these pathophysiological effects are mediated by the 5-HT2A subtype.…”

Section: Received January 28 2002 Accepted May 30 2002mentioning

confidence: 99%

Effects of Sarpogrelate, a Novel 5-HT2 Antagonist, on 5-HT-Induced Endothelium-Dependent Relaxations in Porcine Coronary Artery

Japanese Journal of Pharmacology

Nakazawa

Nagatomo

2002

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ABSTRACT-The aim of the present study was to examine the effects of sarpogrelate, a 5-HT2 antagonist, on 5-HT-induced endothelium-dependent relaxation in isolated porcine coronary artery preincubated with ketanserin (3´10 -6 M) and precontracted by U 46619 (5´10 -9 M) and compare its effects with other 5-HT2 antagonists such as ritanserin and cyproheptadine. The investigation showed that sarpogrelate (10 -7 -10 -5 M) had a weak antagonistic effect on 5-HT-induced relaxation and its effect was weaker than that of ritanserin (10 -9 -10 -7 M) and cyproheptadine (10 -8 -10 -6 M). The rank order of the antagonistic effects was: ritanserin > cyproheptadine > sarpogrelate. The study also showed that both sarpogrelate and ritanserin had no inhibitory effect on bradykinin-induced relaxation. In our previous study, we investigated the binding affinity of sarpogrelate, ritanserin and cyproheptadine to the 5-HT2A-receptor in rabbit cerebral cortex membranes and the pKi values found were 7.22, 8.98 and 7.54, respectively (M. Rashid et al., Jpn J Pharmacol 87, 189 -194, 2001). Rank order of the calculated ratio of concentration of pA2 or pD¢2 vs Ki was: sarpogrelate > ritanserin > cyproheptadine. Thus, these findings suggest that sarpogrelate has the lowest antagonistic effect on 5-HT-induced endothelium-dependent relaxation and the highest selectivity towards 5-HT2A receptor and might also be the safest drug with respect to its clinical implications in comparison with ritanserin and cyproheptadine.Keywords: Sarpogrelate, Porcine coronary artery, Endothelium-dependent relaxation, 5-HT receptor Recent studies have revealed that serotonin (5-HT) has produced both contractions and a relaxation response in the vascular smooth muscles (1 -4). Multiple 5-HT receptors are involved in mediating these effects. 5-HT-induced vasoconstrictions of arteries are mainly mediated by 5-HT2A receptor subtype (5). 5-HT causes both endotheliumdependent and endothelium-independent relaxation of a number of isolated blood vessels in a variety of animals. In porcine coronary and pulmonary artery, 5-HT causes endothelium-dependent relaxation responses. So far, it has been reported that endothelium-dependent relaxant effects of 5-HT in pig coronary and pulmonary artery are mediated by 5-HT1-like and /or 5-HT2B receptors (6 -9).Sarpogrelate has been demonstrated to be selective and to show high affinity for the 5-HT2A receptor subtype, since it lacks significant 5-HT1, 5-HT3, 5-HT4; =1-, =2-and > -adrenoreceptor; histamine H 1 and H 2 ; and muscarinic M 3 antagonistic activity (10 -12). Sarpogrelate was introduced as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis (13). Sarpogrelate inhibits thrombus formation (14, 15) and suppresses platelet aggregation (16,17). It inhibits 5-HT induced coronary artery spasm (18) and contraction of coronary artery in the porcine model mediated by 5-HT and = -methylserotonin (19) and also inhibits vascular smooth muscle cell proliferation (20). All of these pathophysiological effe...