Pharmacological analysis of the hypothermic effects of NAN-190 and its analogs, postsynaptic 5-HT1A receptor antagonists, in mice.
In this study, we examined the role of 5-hydroxytryptamine (5-HT)1A and alpha1-adrenergic receptors in the hypothermia induced by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190) and its analogs, 1-(2-methoxyphenyl)-4-[(4-succinimido)butyl]piperazine (MM77) and trans-1(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]piperazine (MP245), which--like NAN-190--showed a high affinity for 5-HT1A and alpha1-adrenoceptors. Administration of NAN-190 (a partial agonist of presynaptic and an antagonist of postsynaptic 5-HT1A receptors and alpha1-adrenoceptors), MM77 and MP245 (antagonists of postsynaptic 5-HT1A receptors), as well as 8-OH-DPAT (a 5-HT1A agonist) and prazosin (an alpha1-adrenoceptor antagonist) induced a dose-dependent hypothermia in mice. The silent antagonist of 5-HT1A receptors, WAY 100635, which abolished the hypothermic effect of 8-OH-DPAT, inhibited the hypothermia induced by NAN-190 administered at a dose of 1 mg/kg (but not 2 mg/kg) and by MP245 (0.5 and 1 mg/kg), but failed to change the MM77 (1 and 4 mg/kg)-induced decrease in body temperature in mice. The alpha1-adrenoceptor agonist St 587, which reduced the hypothermic effect of prazosin, inhibited the decrease in body temperature evoked by NAN-190 at the higher dose and by MP245 at both the doses used, but did not affect the MM77-induced hypothermia in mice. The obtained results suggest that the hypothermia in mice induced by NAN-190 and its constrained analog MP245 is connected with stimulation of 5-HT1A receptors and with blockade of alpha1-adrenoceptors, participation of these receptors not being equivalent, though. The origin of the hypothermia evoked by MM77 is still unknown.
Wesołowska
Anna
A
Department of New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Borycz
Jolanta
J
Paluchowska
Maria H
MH
Chojnacka-Wójcik
Ewa
E
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D010879:Piperazines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine