Stereoselective blockade at the 5-HT autoreceptor and inhibition of radioligand binding to central 5-HT recognition sites by the optical isomers of methiothepin.
The enantiomers of the 5-HT autoreceptor antagonist methiothepin have been prepared and their activity as antagonists of the 5-HT autoreceptor and at the 5-HT recognition sites present in the frontal cortex of the rat have been evaluated. At the 5-HT autoreceptor, the order of potency as antagonists of 5-HT was (+)methiothepin (apparent pA2 5.95) less than (+/-)methiothepin (apparent pA2 6.62) less than or equal to (-)methiothepin (apparent pA2 6.81). At the 5-HT2 recognition site, the isomeric forms of methiothepin were potent (pIC50 approximately 8.2) and equiactive. At the subtypes of the 5-HT1 recognition sites, similar concentrations to those blocking the autoreceptor were effective and (+)methiothepin was less active than (-)methiothepin. It is concluded that the chiral association of methiothepin with the 5-HT autoreceptor provides further evidence for a pharmacological similarity between this receptor and the 5-HT1B subtype of the 5-HT1 recognition site.
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D003988:Dibenzothiepins / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007650:Ketanserin; D008297:Male; D008719:Methiothepin / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D003988:Dibenzothiepins; D010880:Piperidines; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D008719:Methiothepin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D007650:Ketanserin