1 We investigated the ability of N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand, to produce anti-anxiety and antidepressant-like effects in various animal models. 2 AC-5216 showed high affinity for MBRs prepared from rat whole brain (K i 0.297 nM), rat glioma cells (IC 50 3.04 nM) and human glioma cells (IC 50 2.73 nM), but only negligible affinity for the other main receptors including central benzodiazepine receptors. 3 AC-5216 produced anti-anxiety effects in the Vogel-type conflict test in rats, and in the light/dark box and social interaction tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg À1 , p.o., respectively. These effects of AC-5216 were antagonized by PK11195, an MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg kg À1 , p.o.) reduced the immobility time, and this effect was blocked by PK11195. 4 AC-5216 had no myorelaxant effects, did not affect the memory or prolong hexobarbitoneinduced sleep in mice, even at doses as high as 1000 mg kg À1 , p.o. Although it did slightly prolong the ethanol-induced sleep time at 1000 mg kg À1 , AC-5216 (1-100 mg kg À1 , p.o.) produced no distinct change in the rat electroencephalogram. 5 These results indicate that AC-5216 produces anti-anxiety and antidepressant-like effects that are mediated by MBR, but does not cause the side effects normally associated with conventional benzodiazepines. Hence, AC-5216 shows potential for the treatment of stress-related disorders including anxiety and depression.
1 The anti-emetic and pharmacological pro®le of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide×2 fumarate), a novel and potent dopamine D 2 , D 3 and 5-hydroxytryptamine-3 (5-HT 3 ) receptors ligand, was investigated in the present study. 2 In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT 3 receptor agonist (pA 2 value of 7.04). Other 5-HT 3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron4 ondansetron=AS-811244metoclopramide.
1 The e ects of two sigma (s) binding site ligands, (+)-pentazocine and 1,3-di-o-tolylguanidine (DTG), on bladder functions were examined in rats. 2 Cystometry using urethane-anaesthetized rats showed that (+)-pentazocine (1 ± 5 mg kg 71 , i.v.) and DTG (1 ± 5 mg kg 71 , i.v.) prolonged micturition intervals, indicating increased bladder capacity and raised the threshold pressure.3 The e ects of (+)-pentazocine (2 mg kg 71 , i.v.) on micturition were not in¯uenced by naloxone (0.5 mg kg 71 , i.v.), which antagonized similar e ects of morphine (2 mg kg 71 , i.v.). 4 When administered intracerebroventricularly (i.c.v.), DTG (1 mg) and (+)-pentazocine (30 mg) prolonged micturition intervals with increased threshold pressure on the cystometrogram. 5 In isolated bladder detrusor strips of rats, (+)-pentazocine (3 mM) and DTG (1 mM) did not a ect contractile responses to electrical ®eld stimulation. A higher concentration of DTG (3 mM) slightly suppressed the response induced by 30 Hz stimulation.6 The e ects of (+)-pentazocine and DTG on micturition were abolished by pre-treatment with pertussis toxin (PTX, 1 mg, i.c.v.). 7 These results indicate that typical s ligands, such as (+)-pentazocine and DTG, increase bladder capacity in anaesthetized rats. Moreover, the mechanism by which s ligands change the urinary storage properties in rats may involve pathways in which the function of Gi/o proteins is necessary.
A series of 3-phenyl-2-piperazinyl-5H-1-benzazepines and related compounds were synthesized and evaluated for potential neuroleptic activity. The preparation of these compounds was carried out by 2,3-dichlorination of 3-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones with phosphorus pentachloride followed by amination and concurrent dehydrochlorination. Compounds having the 4-chloro or 4-fluoro substituent in the 3-phenyl group were found to possess the neuroleptic-like activity. Among them, 2-(4-methyl-1-piperazinyl)-3-(4-fluorophenyl)-5H-1-benzazepine dihydrochloride (23) was comparable to chlorpromazine in inhibiting exploratory activity, conditioned avoidance response, and self-stimulation response and more potent than chlorpromazine in antagonizing apomorphine-induced emesis. These neuroleptic effects may be based on an antidopaminergic property of the compound. In causing catalepsy or ptosis, however, 23 was weaker than chlorpromazine. Therefore, this ring system is of interest as a novel class of neuroleptics. Some compounds having the 7-chloro or 7-bromo substituent showed potent anticonvulsant effects against maximal seizures induced by electroshock or pentylenetetrazole.
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