Effects of WAY 100635 and (-)-5-Me-8-OH-DPAT, a novel 5-HT1A receptor antagonist, on 8-OH-DPAT responses.
The neurochemical profile at both post and presynaptic 5-HT1A receptors of a novel 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) analog, 5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin ¿(+/-)-5-Me-8-OH-DPAT¿ and its stereoisomers was determined and compared to that of the highly selective 5-HT1A receptor antagonist, N-[4-(2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide (WAY 100635). We evaluated their effects on 8-OH-DPAT-induced decrease in cAMP production, on 8-OH-DPAT-induced decrease in rat ventral hippocampal extracellular 5-hydroxytryptamine (5-HText) levels and in body temperature in mice. Both (+/-)- and (-)-5-Me-8-OH-DPAT blocked the 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP production. Moreover, while having no significant effect when injected alone, (+/-)-, (-)-5-Me-8-OH-DPAT and WAY 100635 antagonized the 8-OH-DPAT-induced decrease in 5-HText in rats and hypothermia in mice. By contrast, the (+) isomer inhibited the cAMP synthesis and did not modify the 8-OH-DPAT response on 5-HText in ventral hippocampus. These data suggest that (+/-)-5-Me-8-OH-DPAT acts selectively, its activity residing in the (-) enantiomer, this latter compound acting similarly to WAY 100635 as a full, selective and silent 5-HT1A antagonist.
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Lab. Neuropharmacol. JE MESR 92-372, Fac. Pharmacie, Institut de Signalisation et Innovation Thérapeutique, Univ. Paris Sud, Châtenay-Malabry, France. a-c.trillat@cep.u-psud.fr
Malagié
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Mathé-Allainmat
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Anmela
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Jacquot
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Langlois
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Gardier
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004347:Drug Interactions; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013237:Stereoisomerism; D013268:Stimulation, Chemical
C113949:5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases