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Centrally acting hypotensive agents with affinity for 5‐HT 1A binding sites inhibit forskolin‐stimulated adenylate cyclase activity in calf hippocampus
Author(s) -
Schoeffter Philippe,
Hoyer Daniel
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11728.x
Subject(s) - ipsapirone , partial agonist , medicine , forskolin , agonist , endocrinology , metergoline , cyclase , chemistry , yohimbine , 5 ht1a receptor , 8 oh dpat , pindolol , pharmacology , receptor , biology , 5 ht receptor , buspirone , antagonist , serotonin
1 A number of centrally acting hypotensive agents and other ligands with high affinity for 5‐hydroxytryptamine 1A (5‐HT 1A ) recognition sites have been tested on forskolin‐stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5‐HT 1A ‐receptors. 2 Concentration‐dependent inhibition of forskolin‐stimulated adenylate cyclase activity was elicited by the reference 5‐HT 1 ‐receptor agonists (mean EC 50 value, n m ): 5‐HT (22), 5‐carboxamidotryptamine (5‐CT, 3.2), 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT, 8.6), N,N‐dipropyl‐5‐carboxamidotryptamine (DP‐5‐CT, 2.3), l‐[2‐(4‐aminophenyl)ethyl]‐4‐(3‐trifluoromethylphenyl)‐piperazine (PAPP or LY 165163, 20), 5‐methoxy‐3‐(l,2,3,6‐tetrahydro‐4‐pyridinyl)−1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). amounted to 18–20% inhibition for all but the latter two agonists (14%). 3 The following hypotensive agents with high affinity for 5‐HT 1A sites were potent agonists in this system (mean EC 50 value, n m ): flesinoxan (24), indorenate (99), erythro‐l‐(1‐[2‐(l,4‐benzodioxan‐2‐yl)−2‐hydroxyethyl]‐4‐piperidyl)−2‐benzimidazolinone (R 28935, 2.5), urapidil (390) and 5‐methylurapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60–80% efficacy. 4 Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2‐(2,6‐dimethoxyphenoxyethyl)aminomethyl‐l,4‐benzodioxane (WB 4101) which bind to 5‐HT 1A sites with nanomolar affinity, were agonists and inhibited potently forskolin‐stimulated adenylate cyclase in calf hippocampus, showing mean EC 50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. 5 Spiperone and methiothepin (each 1 μ m ) caused rightward shifts of the concentration‐effect curve to 8‐OH‐DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 μ m ) and the (−)− and (+)‐enantiomers of pindolol (1 μ m and 0.1 mM, respectively). 6 There was an excellent correlation ( r = 0.90, P = 0.0001) between the pEC 50 values (ranging from 6.4 to 8.7) of the 19 agonists tested at adenylate cyclase and their pK D for 5‐HT 1A recognition sites. Apparent pK B values of antagonists at adenylate cyclase and their pK D values for 5‐HT 1A binding sites were also significantly correlated. 7 This study further indicates that the 5‐HT 1A recognition site and the 5‐HT receptor mediating inhibition of adenylate cyclase in hippocampus are the same. The data show that a number of centrally acting hypotensive agents with high affinity for the 5‐HT 1A site are potent agonists in this model, suggesting an involvement of central 5‐HT 1A ‐receptors in the control of blood pressure.