Inhibition by 5-HT of forskolin-induced cAMP Formation in the renal opossum Epithelial cell line OK: Mediation by a 5-HT 1B like receptor and antagonism by methiothepin

Abstract

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-HT 1B (pindolol, propranolol, cyanopindolol, SDZ 21,009 and isamoltane) or 5-HT 1D 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 μM 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 β-adrenergic receptor blockers cyanopindolol, SDZ 21,009, (−)-pindolol and (−)-propranolol, and the α 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-HT 1B receptor, although differences are apparent with regard to potencies of some compounds. Methiothepin is probably the only effective antagonist at 5-HT 1B receptor sites, whereas the described putative 5-HT 1B receptor antagonists have to be considered as partial agonists, yielding agonist or antagonist activity depending on the system that is studied.