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Wesolowska A, Paluchowska MH, Golembiowska K, Chojnacka-Wojcik E: Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats. J Pharm Pharmacol. 2003 Apr;55(4):533-43.
The purpose of this study was to further characterize the pharmacological effects of MP349 (trans-1-(2-methoxyphenyl)-4-(4-succinimidocyclohexyl) piperazine), a new serotonin 5-HT (1A) postsynaptic receptor antagonist, using several biochemical and behavioural assays. The silent 5-HT (1A)-receptor antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide) was used as a reference compound in in-vivo tests, and diazepam served as standard anxiolytic drug in animal models of anxiety. In this study we showed that MP349 bound with moderate affinity (K (i) = 234 nM) for alpha (1)-adrenoceptors, and with very low affinity (K (i) > 2600 nM) for 5-HT (2A), dopamine D (1), D (2) and benzodiazepine receptors. The effects of MP349 on presynaptic 5-HT (1A) receptors were studied in two models (mice and rats). Like WAY 100635, MP349 antagonized the hypothermia induced by the 5-HT (1A)-receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in mice. Neither MP349 nor WAY 100635 administered alone induced hypothermia. In a rat microdialysis study, MP349 (like WAY 100635) did not affect 5-HT dialysate level in the prefrontal cortex; however, when given before 8-OH-DPAT, it inhibited the decrease in 5-HT release induced by the 5-HT (1A ) agonist. The data demonstrated that MP349 behaved like a functional antagonist of presynaptic 5-HT (1A) receptors. The potential anxiolytic activity of MP349 and reference drugs was examined in a conflict drinking test in rats, a plus-maze test in rats and a four-plate test in mice. MP349 and WAY 100635 produced anxiolytic-like effects, though somewhat weaker than those induced by diazepam, and only in the case of diazepam the anxiolytic-like effects were dose-dependent. Moreover, MP349 administered in doses inducing anxiolytic-like effects did not disturb the locomotor activity (open field test) or locomotor coordination (rota-rod test) of rats. These and earlier results indicated that MP349 was an antagonist of 5-HT (1A) receptors which exhibited anxiolytic-like activity in an animal model of anxiety. |
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