5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine, rauwolscine and some beta-adrenoceptor antagonists.
5-Hydroxytryptamine1B (5-HT1B) receptor mediated-inhibition of forskolin-stimulated adenylate cyclase activity in rat substantia nigra was characterized pharmacologically and compared to 5-HT1D receptor mediated-inhibition of forskolin-stimulated adenylate cyclase activity in calf substantia nigra. Special attention was paid to the effects of drugs known to bind with high affinity to 5-HT1B (pindolol, propranolol, cyanopindolol, SDZ 21-009, isamoltane) or 5-HT1D recognition sites (yohimbine, rauwolscine). pEC50 or pKB values of a variety of 5-HT-receptor ligands (6 agonists including 5-HT, and 12 antagonists) for the inhibition of adenylate cyclase activity in rat substantia nigra, correlated significantly to the corresponding pKD values at 5-HT1B binding sites (r = 0.90, P = 0.0001). Amongst the alpha 2- and beta-adrenoceptor antagonists tested, none of the drugs expressed more than 35% of the intrinsic activity of 5-HT at 5-HT1B receptors. When tested as antagonists, their pKB values were in good agreement with their pKD values for 5-HT1B sites. By contrast, these drugs displayed marked intrinsic activity at 5-HT1D receptors: their pEC50 values were close to their pKD values for 5-HT1D sites and their effects could be potently antagonized by methiothepin. The rank orders of potency of the tested compounds at 5-HT1B and 5-HT1D were markedly different. The results strengthen the identity between 5-HT receptors mediating inhibition of adenylate cyclase activity in rat and calf substantia nigra and 5-HT1B and 5-HT1D binding sites, respectively. They underline the differences between these receptors in terms of intrinsic activities and potencies of drugs.
Schoeffter
P
P
Preclinical Research, Sandoz Ltd, Basel, Switzerland.
Hoyer
D
D
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D000319:Adrenergic beta-Antagonists; D011985:Receptors, Serotonin; D005576:Colforsin; D015016:Yohimbine; D000262:Adenylyl Cyclases