Trishomocubanes: Novel σ ligands modulate cocaine-induced behavioural effects

Abstract

Trishomocubane analogues TC1 ( N-(3′-fluorophenyl)ethyl-4-azahexacyclo [5.4.1.0 2,6.0 3,10.0 5,9.0 8,11]dodecan-3-ol) and TC4 ( N-(3′-fluorophenyl)methyl-4-azahexacyclo [5.4.1.0 2,6.0 3,10.0 5,9.0 8,11]dodecan-3-ol) were evaluated for their modulatory effects on locomotor activity as well as interactions with cocaine-induced responses. TC1 and TC4 have high affinity and moderate to high selectivity for σ 1 (Ki = 10 nM, σ 1/ σ 2 = 0.03) and σ 2 (Ki = 20 nM, σ 1/ σ 2 = 7.6) receptor subtypes respectively. Both compounds have negligible affinity for the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. In behavioural studies, TC1 produced a dose-related inhibition in spontaneous locomotor activity measured in a Digiscan apparatus. TC1 attenuated the stimulatory locomotor effect of 20 mg/kg cocaine with a half-maximal depressant activity (ID 50) of 38.6 mg/kg. TC1 (dose range of 25 to 100 mg/kg) also partially substituted for the effect of cocaine (10 mg/kg) in a discriminative stimulus task, involving the trained discrimination between cocaine and saline using a two-lever choice method. Following a dose of 50 mg/kg TC1, a maximum of 31% substitution was reached. The response rate was reduced to 56% of vehicle control following a TC1 dose of 100 mg/kg. These behavioural effects suggest that TC1 can act as an antagonist via the σ 1 receptor. In contrast to TC1, TC4 produced a stimulant effect in locomotor activity with the ED 50 estimated at 0.94 mg/kg. In addition, TC4 failed to inhibit cocaine-induced stimulation; neither did it substitute for the discriminative stimulus effects of cocaine. TC4 thus appears to interact predominantly with the σ 2 receptor subtype ( σ 1/ σ 2 = 7.6) which may result in dopamine stimulation independent of the effects of cocaine. The differential effect of TC1 and TC4 warrants further study of the mechanism of these actions. Present data also suggests a potential role for trishomocubane analogues in developing medication or research tools for cocaine addiction.