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S 14506: A novel, potent, high‐efficacy 5‐HT1A agonist and potential anxiolytic agent

The studies characterized the newly discovered 7‐methoxy naphtylpiperazine S 14506 and examined the possible relationship between the apparent in vivo efficacy of 5‐HT1A ligands and the magnitude of their anxiolytic potential. In vitro radioligand binding studies indicated S 14506 to bind with high affinity and in an apparently competitive manner to 5‐HT1A sites, while having much less affinity for other 5‐HT binding sites. S 14506 demonstrated exceptional anxiolytic potential in the pigeon conflict procedure; the magnitude of its effects exceeded that of the other 5‐HT1A ligands 8‐hydroxy‐2‐(n‐propylamino) tetralin (8‐OH‐DPAT), (+)‐flesinoxan, buspirone, and BMY 7378. The anticonflict action of S 14506 was antagonized by the 5‐HT1A antagonist (–)‐alprenolol. Like the prototypical 5‐HT1A agonist 8‐OH‐DPAT, S 14506 induced forepaw treading, hypothermia and spontaneous tail flicks, antagonized morphine‐induced analgesia, and produced stimulus generalization in rats discriminating 8‐OH‐DPAT from saline. The apparent in vivo efficacy of the 5‐HT1A ligands in stimulating corticosterone release varied as follows: S 14506 > 8‐OH‐DPAT > (+)‐flesinoxan > buspirone > BMY 7378. This rank order corresponded with the rank order of magnitude of the anxiolytic action which the same compounds produced in the pigeon conflict procedure. The rank order of in vivo potency of these compounds in producing 5‐HT1A agonist actions in rodents. (i.e., S 14506) > 8‐OH‐DPAT > (+)‐flesinoxan > bus‐pirone > BMY 7378) also corresponded with their rank order of potency in producing anticonflict effects. The data characterize S 14506 as an extremely potent, orally active, high‐efficacy agonist at 5‐HTl1A receptors that demonstrates exceptional anxiolytic potential in the pigeon conflict procedure. The results provide strong evidence that the activation of central nervous system (CNS) 5‐HT1A receptors yields marked anticonflict effects and that the anxiolytic potential of 5‐HT1A ligands is proportional to their efficacy at 5‐HT1A re‐ceptors. © 1992 Wiley‐Liss, Inc.