Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats.
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)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 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.
Wesołowska
Anna
A
Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Smetna 12, Poland.
Paluchowska
Maria H
MH
Gołembiowska
Krystyna
K
Chojnacka-Wójcik
Ewa
E
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D014151:Anti-Anxiety Agents; D003975:Diazepam; D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D017367:Selective Serotonin Reuptake Inhibitors; C479465:MP349; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide