N-(1-Methyl-5-indolyl)-N'-(3-pyridyl)urea hydrochloride: the first selective 5-HT1C receptor antagonist

Abstract

The 5-HTic receptor was first characterized by Pazos1 in 1984. It is present in high levels in the choroid plexus epithelial cells with at least 10-fold lower densities in other brain regions of both rat2 and humans3•4 and is linked to the phosphatidyl inositol hydrolysis secondary messenger system5•6 as is the 5-HT2 receptor.5•7 In addition to sharing the same secondary messenger system, both the 5-HTic and 5-HT2 receptors have similar gene sequences with 79% homology in the seven transmembrane domains in rat8 and 80% in humans.9 This accounts for the very similar pharmacological profile of both receptors. Thus most of the "classical" 5-HT receptor antagonists such as methysergide, metergoline, mianserin, and cyproheptadine have similar affinities for both receptors, while some, such as spiperone, ketanserin, and pirenperone, are 5-HT2 selective.7 Only two antagonists have been reported to show modest 5-HTic receptor selectivity compared with the 5-HT2 site: 1-naphthylpiperazine (1-NP) and LY 53857 (10-and 5-fold, respectively).7 The former compound * To whom correspondence should be addressed.

Mediation by 5‐hydroxytryptamine2B receptors of endothelium‐dependent relaxation in rat jugular vein

“…Schild regression analysis yielded pA2 estimates of 7.2 for SB 200646 and 7.3 for mianserin (Figures 2 and 3). The slopes of the regression were 1.05 and receptors (pKi = 6.86; Forbes et al, 1993). The finding that yohimbine also possessed antagonist activity in rat jugular vein at concentrations consistent with its pA2 at 5-HT2B receptors permits further definition of the subtype involved.…”

“…We have recently demonstrated that a novel ligand, SB 200646 (N-1-methyl-5-indolyl)-N'-(3-pyridyl) urea HCI) exhibits moderate affinity for cloned rat 5-HT2c receptors and putative 5-HT2B receptors in rat stomach fundus, but little or no affinity for rat 5-HT2A and many other 5-HT receptors (Forbes et al, 1993;Baxter et al, 1994 (Bodelsson et al, 1992) for the 2nd agonist concentration-effect curve by that for the 1st concentration-effect curve constructed in the presence and absence of antagonist respectively. Tissues were equilibrated with antagonists for 1 h before the construction of second concentration-effect curves.…”

Serotonin receptors: Subtypes, functional responses and therapeutic relevance

“…It seems, therefore, that additional properties of these antimigraine drugs, for example, the vasoconstriction in the extracerebral cephalic circulation with methysergide, ergotamine and dihydroergotamine (partly via 5-HT,-like receptors) and the antidepressant action with pizotifen, may be involved in their therapeutic action . Based mainly on the ability of a 5-HT,e receptor agonist, m-chloro-phenyl piperazine, to elicit migraine-like headaches in some patients and the ability of drugs such as mianserin to block this receptor, it has been advocated that 5-HTZc receptor antagonism is important for antimigraine action (Fozard and Gray, 1989;Fozard, 1992;Kennett, 1993). It should be noted, however, that m-chloro-phenyl-piperazine is not a selective agent and drugs that block the 5-HTzc receptor (e.g.…”

Strain-dependent effects of diazepam and the 5-HT2B/2C receptor antagonist SB 206553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze

“…The initial use of nonselective antagonists for 5-HT 2B/2C receptors (3,4), followed by analysis of the behavioral effects of SB R.N. Takahashi et al 200646A, a selective, albeit weak, antagonist of these receptors (5), has indicated that blockade of 5-HT 2B/2C receptors may actually be endowed with anxiolytic properties (6). Such an intrinsic property of 5-HT 2B/2C receptor antagonists has raised interest with regard to the therapy of anxiety disorders.…”