Inhibition by 5-HT of forskolin-induced cAMP formation in the renal opossum epithelial cell line OK: mediation by a 5-HT1B like receptor and antagonism by methiothepin.
The functional activity of various 5-HT receptor agonists, including 5-CT, sumatriptan, CP 93, 129 and 1-naphtylpiperazine, and of drugs known to bind with high affinity to 5-HT1B (pindolol, propranolol, cyanopindolol, SDZ 21,009 and isamoltane) or 5-HT1D binding sites (yohimbine and rauwolscine) was measured at 5-HT receptors that are negatively coupled to adenylate cyclase in cultures of the renal epithelial cell line OK. 5-HT receptor-mediated inhibition of adenylate cyclase was studied by measuring inhibition of cAMP formation, induced by 100 microM forskolin. Besides 5-HT, various other compounds with affinity for 5-HT receptors behaved as agonists with the following rank order of potency: RU 24,969 > 5-CT > dihydroergotamine = 5-HT > CP 93,129 > d-LSD > 1-naphtylpiperazine > sumatriptan > TFMPP = mCPP > CGS 12066B = metergoline > methysergide. The beta-adrenergic receptor blockers cyanopindolol, SDZ 21,009, (-)-pindolol and (-)-propranolol, and the alpha 2-adrenergic blockers yohimbine and rauwolscine yielded agonist activity at nanomolar and micromolar concentrations, respectively. Isamoltane acted as a partial agonist. Methiothepin was the only compound that antagonised the OK cell 5-HT receptor-mediated inhibition of forskolin-induced cAMP formation. We conclude that the OK cell 5-HT receptor has properties consistent with a 5-HT1B receptor, although differences are apparent with regard to potencies of some compounds. Methiothepin is probably the only effective antagonist at 5-HT1B receptor sites, whereas the described putative 5-HT1B receptor antagonists have to be considered as partial agonists, yielding agonist or antagonist activity depending on the system that is studied.
Pauwels
P J
PJ
Laboratory of Cellular Neurobiology, Centre de Recherche Pierre Fabre, Castres, France.
Palmier
C
C
D058669:Adrenergic alpha-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008719:Methiothepin / Q000494:pharmacology*; D009893:Opossums / Q000378:metabolism*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012756:Sheep
D058669:Adrenergic alpha-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D005576:Colforsin; D012701:Serotonin; D008719:Methiothepin; D000242:Cyclic AMP