Pharmacological properties of SM-3997: A new anxioselective anxiolytic candidate.

Abstract

Abstract-Pharmacologicalproperties of SM-3997 (3aa,4Q,7(9,7aa-hexahydro-2 (4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-4,7-methano-1 H-isoindole-1,3(2H) dione dihydrogen citrate) have been examined in rats and mice. SM-3997 showed a dose-related anticonflict activity in rats in a water lick conflict paradigm, and it had no effect on water consumption in a spontaneous water drinking test. The potency of SM-3997 appeared to be equal to that of buspirone and about one-half that of diazepam.No tolerance to the anticonflict activity of SM-3997 was observed following 5 and 10 consecutive days of treatment. Unlike diazepam, SM-3997 had no anticonvulsant effect and had very weak muscle relaxant and hypnotic effects.On the other hand, SM-3997 and buspirone exhibited dopamine antagonistic action, although the potency of SM-3997 was less than one fourth that of buspirone.These results show that SM-3997 is a new anxioselective anxiolytic agent which is weaker than buspirone in the dopaminergic neuron system.

Anticonflict Action of Tandospirone in a Modified Geller-Seifter Conflict Test in Rats.

“…All other azapirones that are clinically effective also bind selectively to 5 HT1A receptors (22). Moreover, we have also demonstrated that tandospirone acts on 5 HT1A receptors as an agonist in behavioral, biochemical and electrophysiological studies (10,19,(23)(24)(25)(26). In the light of these facts, the possibility exists that the agonist action of tandospirone on 5-HT1A receptors, but not benzodiazepine receptors, is related to its con flict effect.…”

“…For example, in rat conflict tests, which are the most widely used animal behavioral para digms for recognizing potential anxiolytic drug activity, some groups, including our own, were able to demonstrate anticonflict activities of azapirones (5,(12)(13)(14), while others failed to find any positive effects (15)(16)(17). Moreover, in the former cases, the efficacies of azapir ones were substantially lower than those of benzodiazepines.…”

“…Lack of muscle relaxant action (5), which diazepam markedly shows, suggests that the mechanism of the decrease in unpunished responding by tandospirone is different from that by diazepam. Since tandos pirone produces 5-HT behavioral syndromes such as flat body posture in rats (10), this ac tion of tandospirone may be related to the de crease in unpunished responding.…”

“…Conventional con flict tests have been mainly developed in stud ies of benzodizepines. Since azapirones differ from benzodiazepines not only in chemical structure but also in pharmacological prop erties (5,18), these tests might be less sensi tive to non-benzodiazepines such as azapir ones. Therefore, the fine differences in test conditions (e.g., shock intensity, degree of de privation and conflict schedule conditions) may have led to the inconsistent results pre viously described.…”

Autoradiographic evidence for the interaction of SM-3997 with 5-HT1A receptors in the rat brain.

“…We previously reported that SM-3997 did not directly interact with GABA receptor/CI channel complexes, but is suggested to have 5-HT1A agonistic properties by pharmacolo gical, biochemical and electrophysiological experiments (1)(2)(3)(4)(5). The present study was conducted to determine the regional distribu tion of 5-HT,,, receptors and SM-3997 binding to these receptors in the rat brain.…”