Shuzo Takehara

The pharmacological properties of Y‐23684, a benzodiazepine receptor partial agonist

1 The pharmacological properties of a benzodiazepine receptor (BZR) partial agonist, Y‐23684 were investigated in comparison with those of diazepam, a conventional BZR full agonist. 2 Y‐23684 and diazepam showed high and selective affinity for the BZR with Ki values of 41 and 5.8 nm, respectively. 3 In contrast to diazepam, variability was noted in the anticonvulsive potency of Y‐23684 depending on convulsants (bicuculline, pentylenetetrazol and maximal electrical shock). Y‐23684 produced the most potent protective effect against bicuculline in rats and mice with ED50s of 1.3 and 1.2 mg kg−1, respectively. 4 In rat conflict models (Geller‐Seifter and water‐lick tests), Y‐23684 produced an antipunishment action at doses 2–4 times lower than diazepam. In contrast to diazepam, Y‐23684 did not affect unpunished responding up to 50 mg kg−1in the Geller‐Seifter test. 5 In other rat models of anxiety (social interaction and elevated plus‐maze tests), Y‐23684 was as efficacious as and ten fold more potent than diazepam. In a mouse model of anxiety (exploration (light/dark box) test), Y‐23684 was as efficacious and two fold less potent as diazepam. In these paradigms, Y‐23684 showed a selective anxiolytic profile over a wide dose‐range without loss of efficacy and sedative action. 6 The impairment of motor coordination (rotarod) and potentiation of CNS depressants (ethanol and hexobarbitone) by Y‐23684 was much weaker than that of diazepam. 7 These results suggest that Y‐23684 would be a potent and selective anxiolytic agent in man with less side‐effects than conventional BZ‐anxiolytics.

Neuropharmacological profile of a novel potential atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)- 6H-[1]benzothieno[2,3-b][1,5] benzodiazepine maleate).

The neuropharmacological profile of Y-931, 8-fluoro-12- (4-methylpiperazin-1-yl)- 6H-[1]benzothieno [2,3-b][1,5]benzodiazepine maleate, was investigated in comparison with those of typical and claimed atypical antipsychotic drugs. Similar to clozapine and olanzapine, Y-931 interacted with multiple neurotransmitter receptors such as dopaminergic, serotonergic, α-adrenergic, muscarinic and histaminergic receptors. Y-931, as well as the other antipsychotics, was active in a dose-dependent manner in established tests which are indicative of potential antipsychotic activity such as inhibition of apomorphine-induced hyperactivity and suppression of conditioned avoidance responses, however, only Y-931 and clozapine were devoid of cataleptogenic potential. In models of N-methyl-D-aspartate (NMDA) receptor hypofunction, Y-931 demonstrated the most potent protective action against the dizocilpine-induced neurotoxicity (neuronal vacuolization) in the rat retrosplenial cortex ([Y-931 (ED50; 0.20 mg/kg, p.o.), olanzapine (1.1), clozapine (5.7), risperidone (6.9), haloperidol (19)). Furthermore, Y-931 and clozapine, unlike the other antipsychotics used, reversed the dizocilpine-induced social deficits at the same doses at which their neuroprotective action was exhibited. The present results suggest that Y-931 may be a novel potential atypical antipsychotic drug with a low risk of extrapyramidal syndrome (EPS) and the property to ameliorate NMDA receptor hypofunction.

N-(2-pyrrolidinylmethyl)benzoxazine-8-carboxamides exhibiting high affinities for All of D2, 5-HT1 A, and 5-HT2 receptors

(R)-N-(1-Benzyl-2-pyrrolidinylmethyl)-6-methylthio-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide exhibited high affinities for all of D2, 5-HT1 A, and 5-HT2 receptors (Ki=0.0042 μM, Ki=0.017 μM, and Ki=0.027 μM, respectively).