Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat.

Since its discovery, the nociceptin/orphanin FQ (N/OFQ)-NOP receptor system has been extensively investigated as a promising target to treat alcoholism. Encouraging results obtained with the endogenous ligand N/OFQ stimulated research towards the development of novel brain-penetrating NOP receptor agonists with a pharmacological and toxicological profile compatible with clinical development. Here we describe the biochemical and alcohol-related behavioral effects of the novel NOP receptor agonist MT-7716. MT-7716 has high affinity for human NOP receptors expressed in HEK293 cells with a Ki value of 0.21 nM. MT-7716 concentration-dependently stimulated GTPγ(35)S binding with an EC50 value of 0.30 nM and its efficacy was similar to N/OFQ, suggesting that MT7716 is a full agonist at NOP receptors. In the two bottle choice test MT-7716 (0, 0.3, 1, and 3 mg/kg, bid) given orally for 14 days dose-dependently decreased voluntary alcohol intake in Marchigian Sardinian rats. The effect became gradually stronger following repeated administration, and was still significant 1 week after discontinuation of the drug. Oral naltrexone (30 mg/kg, bid) for 14 days also reduced ethanol intake; however, the effect decreased over the treatment period and rapidly disappeared when drug treatment was discontinued. MT-7716 is also effective for preventing reinstatement caused by both ethanol-associated environmental stimuli and stress. Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet. MT-7716 significantly attenuated somatic alcohol withdrawal symptoms. Together these findings indicate that MT-7716 is a promising candidate for alcoholism treatment remaining effective with chronic administration.

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

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, alpha-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 (ED(50); 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.