Centrally acting hypotensive agents with affinity for 5‐HT1A binding sites inhibit forskolin‐stimulated adenylate cyclase activity in calf hippocampus

Abstract

A number of centrally acting hypotensive agents and other ligands with high affinity for 5‐hydroxytryptamine1A (5‐HT1A) recognition sites have been tested on forskolin‐stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5‐HT1A‐receptors. Concentration‐dependent inhibition of forskolin‐stimulated adenylate cyclase activity was elicited by the reference 5‐HT1‐receptor agonists (mean EC50 value, nm): 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%). The following hypotensive agents with high affinity for 5‐HT1A sites were potent agonists in this system (mean EC50 value, nm): 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. 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‐HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin‐stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. Spiperone and methiothepin (each 1 μm) 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 μm) and the (−)− and (+)‐enantiomers of pindolol (1 μm and 0.1 mM, respectively). There was an excellent correlation (r = 0.90, P = 0.0001) between the pEC50 values (ranging from 6.4 to 8.7) of the 19 agonists tested at adenylate cyclase and their pKD for 5‐HT1A recognition sites. Apparent pKB values of antagonists at adenylate cyclase and their pKD values for 5‐HT1A binding sites were also significantly correlated. This study further indicates that the 5‐HT1A 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‐HT1A site are potent agonists in this model, suggesting an involvement of central 5‐HT1A‐receptors in the control of blood pressure. 1988 British Pharmacological Society