RECEPTOR-BINDING PROFILE AND ANXIOLYTIC-TYPE ACTIVITY OF DERAMCICLANE(EGIS-3886) IN ANIMAL-MODELS

The present series of experiments was done to characterize the propert ies of deramciclane, a new antiserotonergic drug, in both receptor bin ding studies in vitro and in a number of anxiolytic, antidepressant, a nd antidopaminergic tests in rodents. A striking property of deramcicl ane was its high affinity to both 5-HT2A and 5-HT2C receptors (K-i = 8 .7-27 nM/I). Deramciclane had also a moderate affinity to dopamine D-2 and sigma receptors but did not interact with any of the adrenergic r eceptors. Deramciclane was active in several animal models predicting anxiolytic efficacy in humans. The active dose range of deramciclane w as narrow in some tests, but generally the active dose range extended from 0.5 mg/kg (1.2 mu mol/kg) to 10 mg/kg (23.9 mu mol/kg). Statistic ally significant results were obtained in Vogel's test (1 mg/kg; 2.4 m u mol/kg), social interaction (0.7 mg/kg; 1.7 mu mol/kg), two-compartm ent box (3 mg/kg; 7.2 mu mol/kg), and marble-burying tests (10 mg/kg; 23.9 mu mol/kg). Although deramciclane as such was not active in the e levated plus maze, it antagonized the anxiogenic effect of the CCK ago nist caerulein in this test, although significantly only at one dose ( 0.5 mg/kg; 1.2 mu mol/kg). Deramciclane (1.4 and 14 mg/kg; 3.3 and 32. 5 mu mol/kg) was active in the learned helplessness paradigm. However, it had no antidepressant activity in tetrabenazine-induced ptosis or forced swimming test at less than or equal to 150 mg/kg (359 mu mol/kg ). Deramciclane elevated serum prolactin levels and brain dopamine met abolites (DOPAC, HVA) only at 20-40 mg/kg (48-96 mu mol/kg). Deramcicl ane up to 40-100 mg/kg (96-239 mu mol/kg) did not modify apomorphine-i nduced climbing, amphetamine-induced hyperlocomotion, or the condition ed avoidance reaction. Swimming-induced grooming was inhibited only by 50 mg/kg (112 mu mol/kg) of deramciclane. Deramciclane reduced the mo tor activity at doses well above the established anxiolytic doses: ED5 0 18 mg/kg; 43 mu mol/kg (rats) and 31.5. mg/kg; 75 mu mol/kg (mice). Based on these results the anxiolytic-type selectivity of deramciclane appears satisfactory and to have a psychopharmacological profile of i ts own. (C) 1997 Wiley-Liss, Inc.