Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist?
The effects of several putative 5-HT1 receptor-subtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(m-trifluoromethylphenyl)piperazine), mCPP (1-(m-chlorophenyl)piperazine), CGS 12066 (7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)- piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5-HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HT1B versus 5-HT1A selective. Quipazine showed equal potency at 5-HT1B and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
Schoeffter
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Preclinical Research, Sandoz Ltd, Basel, Switzerland.
Hoyer
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D008297:Male; D010761:Phosphorus Radioisotopes; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D015290:Second Messenger Systems; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013552:Swine
D007295:Inositol Phosphates; D008024:Ligands; D010761:Phosphorus Radioisotopes; D010879:Piperazines; D011985:Receptors, Serotonin; D005576:Colforsin; D000262:Adenylyl Cyclases