Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes.
1) The binding characteristics of [3H]5-HT (5-hydroxytryptamine, serotonin) were investigated in membrane preparations of several regions from calf, pig and human brain in the presence of 100 nmol/l 8-OH-DPAT (8-hydroxy-2[di-n-dipropylamino]tetralin) and 100 nmol/l mesulergine in order to mask 5-HT1A and 5-HT1C sites. 2) [3H]5-HT bound rapidly, reversibly and stereo-selectively to a population of high affinity recognition sites in membranes from pig caudate, calf caudate and human cortex, caudate and substantia nigra. 3) Saturation experiments carried out with [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and 100 nmol/l mesulergine revealed that non-5-HT1A non-5-HT1C sites represented from 50 to more than 90% of the total 5-HT1 sites (determined with [3H]5-HT in the absence of 8-OH-DPAT and mesulergine), depending on the tissue source. 4) The pharmacological profile of these sites was characterized in competition experiments performed with a variety of ligands in membranes of calf, pig and human caudate membranes. Under these conditions, [3H]5-HT labelled a population of "5-HT1-like" sites which display nanomolar affinity for tryptamines (5-carboxamidotryptamine greater than 5-HT greater than or equal to 5-methoxytryptamine greater than tryptamine) and some ergolines (metergoline greater than methysergide). In contrast, these sites showed low affinity for drugs with high affinity and/or selectivity for 5-HT1A (8-OH-DPAT, buspirone), 5-HT1B (21-009, RU 24969), 5-HT1C (mesulergine, mianserin) and 5-HT2 sites (ketanserin, cinanserin).(ABSTRACT TRUNCATED AT 250 WORDS)
Waeber
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Preclinical Research, Sandoz Ltd, Basel, Switzerland.
Schoeffter
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Palacios
J M
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Hoyer
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008566:Membranes / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D000978:Antiparkinson Agents; D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C031649:mesulergine