SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at
dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors.
SSR181507 antagonized
apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked
D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice.
SSR181507 did not induce
catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.)
haloperidol-induced
catalepsy.
SSR181507 was also active in two models sensitive to
antidepressant/
anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a
lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a
saccharin solution. Furthermore,
SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with
antidepressants. Coadministration of the selective 5-HT(1A) blocker
SL88.0338 produced
catalepsy and antagonized the effects of
SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on
SSR181507, and is responsible for its
antidepressant/
anxiolytic properties. Finally,
SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of
SSR181507 suggests that it should control the symptoms of
schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of
antidepressant/
anxiolytic activities.