Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands

The experiments in this study compared the pharmacological properties of se veral BZ-omega receptor ligands, including the imidazobenzodiazepine imidaz enil, the beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido[1, 2-a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative S X-3228, with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [H -3]flumazenil binding nonselectively in membranes from rat cerebellum and s pinal cord, two brain areas enriched in the BZ-omega(1) and BZ-omega(2) rec eptor subtypes, respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in displacing [H-3]flumazenil binding to membranes from r at cerebellum than from spinal cord or hippocampus, indicating selectivity for the BZ-omega(1) receptor subtype. The in vivo experiments showed that a ll compounds increased the latency to clonic seizures produced by isoniazid . However, the maxima; increase in latency induced by diazepam, clobazam, a becarnil, RWJ 46771 and SX-3228 was greater than that of bretazenil, imidaz enil and Y-23684, thereby indicating that these latter compounds have low i ntrinsic efficacy. In the punished drinking, the punished lever pressing an d the elevated plus-maze tests in rats, three models of anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects but at doses which were close to those producing hypolocomotion, ataxia and myorelaxati on as measured in activity cages, the rotarod and the loaded grid tests, re spectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like act ivity at much lower doses than those which impaired motor performances. The magnitude of the positive effects of Y-23684 was similar to that of the re ference BZs, suggesting that it may become a valuable alternative to curren tly used agents for the treatment of anxiety disorders. Abecarnil, RWJ 4677 1 and SX-3228 produced weaker or non-specific anxiolytic-like effects as th ey decreased anxiety-related behaviours at doses similar or close to those impairing motor performance. However, unlike the other compounds they induc ed myorelaxation at doses which were 3-10 times higher than those needed to produce decrease in exploratory activity. It is suggested that the behavio ural profiles of abecarnil, RWJ 46771 and SX-3228 may be attributed to thei r selectivity for the BZ-omega(1) receptor subtype which may account for th eir sedative activity, thereby masking other effects including anxiolytic-l ike activity. This suggests that BZ receptor modulation of anxiety may invo lve BZ receptor subtypes other than BZ-omega(1). (C) 1999 Lippincott Willia ms & Wilkins.