Pharmacological characterization of MP349, a novel 5-HT_1A-receptor antagonist with anxiolytic-like activity, in mice and rats

Abstract

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-(2–1-piperazinyl]ethyl)-N-pyridinyl)cyclohexanecarboxamide) 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 α-adrenoceptors, and with very low affinity (K_i > 2600 nm) for 5-HT_2A, dopamine D₁, D₂ 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 functonal 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.