Detail of "158942-04-2"

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The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Beattie, D. T.; Smith, J. A. M.; Marquess, D.; Vickery, R. G.; Armstrong, S. R.; Pulido-Rios, T.; McCullough, J. L.; Sandlund, C.; Richardson, C.; Mai, N.; Humphrey, P. P. A. (Theravance, Inc.There are some reagents with their cas registry numbers 158942-04-2 and 189188-57-6 are used in this study., South San Francisco, CA 94080, USA). British Journal of Pharmacology, 143(5), 549-560 (English) 2004 Nature Publishing Group. CODEN: BJPCBM. ISSN: 0007-1188. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clin. efficacy in disorders assocd. with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi = 7.5, 8.4 and 7.0, resp.). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi = 8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. Tegaserod (0.1-3 mM) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2 = 8.3), consistent with 5-HT2B receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50 = 8.6), as well as 5-HT4 receptor-mediated relaxation of the rat isolated esophagus (mean pEC50 = 8.2) and contraction of the guinea-pig isolated colon (mean pEC50 = 8.3). Following s.c. administration, tegaserod (0.3 or 1 mg kg-1) inhibited contractions of the stomach fundus in anesthetized rats in response to i.v. dosing of a-Me 5-HT (0.03 mg kg-1) and BW 723C86 (0.3 mg kg-1), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg-1 s.c.) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concns. similar to those that activate 5-HT4 receptors. It remains to be detd. whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clin. profile. .

5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide

All Rights Reserved. 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide. Gresch, Paul J.; Barrett, Robert J.; Sanders-Bush, Elaine; Smith, Randy L. (Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA). Journal of Pharmacology and Experimental Therapeutics, 320(2), 662-669 (English) 2007 American Society for Pharmacology and Experimental Therapeutics. CODEN: JPETAB. ISSN: 0022-3565. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) D-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systematically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, ±1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 mg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 mg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)2A receptor antagonist R-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine- methanol (M100907; 0. 74050-98-9 and 158942-04-2 which are cas registry numbers of substances are two of reagents here.4 mg/kg) blocked the discriminative cue of LSD (0.375 mg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 mg/ml/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT2A receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD. .