Receptor inverse agonists

FIGURE 11.2 Paired experimental data. Values of constitutive calcitonin receptor activity [1 -(Tr/Tj) units] in transiently transfected melanophores. Five separate experiments are shown. Points to the left indicate the basal level of constitutive activity before (filled circles) and after (open circles) addition of 100 nM AC512 (calcitonin receptor inverse agonist). Lines join values for each individual experiment. Points to the right are the mean values for constitutive activity in control (filled circles) and after AC512 (open circles) for all five experiments (bars represent standard errors of the mean). Data shown in Table 11.3. 

Excessive activity of an endogenous ligand which is a benzodiazepine receptor inverse agonist and induces anxiety. In this case, the administration of fiumazenil should relieve anxiety in anxious patients and have no, or sedative, effects in healthy subjects. 

Pimavanserin tartrate (40, ACP-103) is a 5-HT2A receptor inverse agonist currently in phase II clinical development as an antipsychotic agent and for insomnia, focused on sleep maintenance, evaluating slow-wave-sleep at doses of 5 and 20 mg [97,98]. 

Chambers MS, attack JR, Broughton HB, CoUinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, PiUai GV, Reeve AJ, MacLeod AM (2003) Identification of a novel, selective GABAa 5 receptor inverse agonist which enhances cognition. J Med Chem 46 2227-2240... 

Pula G, Mundell SJ, Roberts PJ, Kelly E (2004) Agonist-independent internalization of metabotropic glutamate receptor la is arrestin- and clathrin-dependent and is suppressed by receptor inverse agonists. J Neurochem 89 1009-1020 Pulvirenti L, Maldonadolopez R, Koob GF (1992) NMDA receptors in the nucleus accimibens modulate intravenous cocaine but not heroin self-administration in the rat. Brain Res 594 327-330... 

The key step in the preparation of a novel class of condensed thiophene based GABA receptor inverse agonists was the cross-coupling of the bromo derivative of the parent system. The 2-pyrrolyl substituent, for example, was... 

Augustine-Rauch KA, Zhang QJ, Leonard JL, et al. Evidence for a molecular mechanism of teratogenicity of SB-236057, a 5-HT1B receptor inverse agonist that alters axial formation. Birth Defects Res. Part A Clin. Mol. Teratol. 2004 70 789-807. 

Chemical classes other than benzodiazepines bind to, and have actions at the various benzodiazepine receptor sites. Notably, there are P-carbolines that have either agonist or inverse agonist actions, with a corresponding pharmacology similar to. or the opposite of typical benzodiazepines (e.g, anxiolytic or anxiogenic actions) see BENZODIAZEPINE RECEPTOR INVERSE AGONISTS. 

Lingford-Hughes. A. (19%) Benzodiazepine receptor inverse agonists. Br.. Clin. Pharmacol.. 41.259. 

SR144528 has greater inverse intrinsic activity than AM630. If this interpretation of the data is valid, it is of course an indication that just as the intrinsic activities of CBi and CB2 receptor agonists can vary from compound to compound, so too the (inverse) intrinsic activities of cannabinoid receptor inverse agonists will not be the same for all such ligands. 

The papers listed in Table 3 and discussed in the preceding paragraph represent in vitro studies, and the question arises whether similar results are also obtained in vivo. This was examined in a series of studies on rats subjected to in vivo microdialysis the ligands under study were administered intraperitoneally or intravenously. Cannabinoids indeed decrease acetylcholine release in the dorsal hippocampus (Mishima et al. 2002). In the studies by Tzavara et al. (2001,2003a), in which cannabinoid agonists were not studied themselves, the CBi receptor inverse agonist SR 141716, which elicits effects opposite in direction to those of cannabi-... 

Vermeuien ES, van Smeden M, Schmidt AW, et ai. Novei 5-HT7 receptor inverse agonists. Synthesis and moiecuiar modeiing of aryipiperazine- and 1,2,3,4-tetrahydroisoquinoiin-based aryisuifonamides. J Med Chem 2004 47 5451-5466,... 

Sternfeld F, Carling RW, Jelly RA, et al. Selective, orally active y-aminobutyric acid(A) as receptor inverse agonists as cognition enhancers. J Med Chem 2004 47 2176-2179. 

Shearman, L.P, Rosko, K.M., Fleischer, R., Wang, J., Xu, S., Tong, X.S. and Rocha, B.A. (2003) Antidepressant-like and anorectic effects of the cannabinoid CBj receptor inverse agonist AM251 in mice, Behav Pharmacol, 14 573-82. 

Wacker, D., Feneilti, G., Brown, M.A., et al. (2010) Conserved binding mode of human p adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc, 132 (33), 11443-11445. 

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