MP-3022, a new putative antagonist at pre- and postsynaptic 5-HT1A receptors.
The receptor binding and pharmacological profile of the new, putative 5-HT1A receptor antagonist MP-3022 (4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)piperazine) were studied. Another 5-HT1A receptor antagonist, (S)-WAY 100135 ((S)-N-tert-butyl-3-[4-(2-methoxyphenyl)piperazine-1-yl]-2- phenylpropanamide), was used as a reference drug in functional models. MP-3022 showed a high affinity (Ki) of 25 nM and 69 nM, respectively, at 5-HT1A binding sites and alpha 1-adrenoceptors in vitro. The Ki values of MP-3022 in relation to other binding sites examined (5-HT2A, alpha 2- or beta-adrenoceptors, dopamine D1 and D2) were 20-100-fold lower. In functional studies, MP-3022 significantly attenuated the 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin)-induced decrease in the population spike evoked in the CA1 cell layer of the hippocampal slice preparation, without producing its own effects. The 8-OH-DPAT-evoked increase in the corticosterone concentration in the serum as well as the 8-OH-DPAT-mediated decrease in the 5-HT turnover in the hippocampus were attenuated by MP-3022. MP-3022 increased the serum corticosterone concentration only at the highest dose used, but it did not change the 5-HT turnover in the hippocampus. Like MP-3022, (S)-WAY 100135 antagonized the 8-OH-DPAT-induced effects. It has also been demonstrated that (S)-WAY 100135 is devoid of an intrinsic activity at 5-HT1A receptors. The data obtained demonstrate that, like (S)-WAY 100135, MP-3022 behaves like a functional antagonist at pre- and postsynaptic 5-HT1A receptors.
Przegaliński
E
E
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Filip
M
M
Bijak
M
M
Wedzony
K
K
Budziszewska
B
B
Tokarski
K
K
Maćkowiak
M
M
Fijał
K
K
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004558:Electric Stimulation; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D014230:Triazoles; C081293:WAY 100135; C088974:4-(3-(benzotriazol-1-yl)propyl)-1-(2-methoxyphenyl)piperazine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone