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.