The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5-HT 2A and 5-HT 2C receptors (K i = 8.7-27 nM/l). Deramciclane had also a moderate affinity to dopamine D 2 and sigma receptors but did not interact with any of the adrenergic receptors.
Deramciclane was active in several animal models predicting anxiolytic efficacy in humans. The active dose range of deramciclane was narrow in some tests, but generally the active dose range extended from 0.5 mg/kg (1.2 µmol/kg) to 10 mg/kg (23.9 µmol/kg). Statistically significant results were obtained in Vogel's test (1 mg/kg; 2.4 µmol/kg), social interaction (0.7 mg/kg; 1.7 µmol/kg), two-compartment box (3 mg/kg; 7.2 µmol/kg), and marble-burying tests (10 mg/kg; 23.9 µmol/kg). Although deramciclane as such was not active in the elevated plus maze, it antagonized the anxiogenic effect of the CCK agonist caerulein in this test, although significantly only at one dose (0.5 mg/kg; 1.2 µmol/kg).
Deramciclane (1.4 and 14 mg/kg; 3.3 and 32.5 µmol/kg) was active in the learned helplessness paradigm. However, it had no antidepressant activity in tetrabenazine-induced ptosis or forced swimming test at ≤150 mg/kg (359 µmol/kg). Deramciclane elevated serum prolactin levels and brain dopamine metabolites (DOPAC, HVA) only at 20-40 mg/kg (48-96 µmol/kg). Deramciclane up to 40-100 mg/kg (96-239 µmol/kg) did not modify apomorphine-induced climbing, amphetamine-induced hyperlocomotion, or the conditioned avoidance reaction. Swimming-induced grooming was inhibited only by 50 mg/kg (112 µmol/kg) of deramciclane. Deramciclane reduced the motor activity at doses well above the established anxiolytic doses: ED 50 18 mg/ kg; 43 µmol/kg (rats) and 31.5. mg/kg; 75 µmol/kg (mice). Based on these results the anxiolytic-type selectivity of deramciclane appears satisfactory and to have a psychopharmacological profile of its own.