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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.JP

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-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.

Authors+Show Affiliations

Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Smetna 12, Poland.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12803776

Citation

Wesołowska, Anna, et al. "Pharmacological Characterization of MP349, a Novel 5-HT1A-receptor Antagonist With Anxiolytic-like Activity, in Mice and Rats." The Journal of Pharmacy and Pharmacology, vol. 55, no. 4, 2003, pp. 533-43.
Wesołowska A, Paluchowska MH, Gołembiowska K, et al. Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats. J Pharm Pharmacol. 2003;55(4):533-43.
Wesołowska, A., Paluchowska, M. H., Gołembiowska, K., & Chojnacka-Wójcik, E. (2003). Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats. The Journal of Pharmacy and Pharmacology, 55(4), 533-43.
Wesołowska A, et al. Pharmacological Characterization of MP349, a Novel 5-HT1A-receptor Antagonist With Anxiolytic-like Activity, in Mice and Rats. J Pharm Pharmacol. 2003;55(4):533-43. PubMed PMID: 12803776.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats. AU - Wesołowska,Anna, AU - Paluchowska,Maria H, AU - Gołembiowska,Krystyna, AU - Chojnacka-Wójcik,Ewa, PY - 2003/6/14/pubmed PY - 2003/12/12/medline PY - 2003/6/14/entrez SP - 533 EP - 43 JF - The Journal of pharmacy and pharmacology JO - J. Pharm. Pharmacol. VL - 55 IS - 4 N2 - 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. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/12803776/Pharmacological_characterization_of_MP349_a_novel_5_HT1A_receptor_antagonist_with_anxiolytic_like_activity_in_mice_and_rats_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3573&date=2003&volume=55&issue=4&spage=533 DB - PRIME DP - Unbound Medicine ER -