SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT 1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Abstract

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 derivative that possesses high and selective affinities for D2-like and 5-HT1A receptors (K1 = 0.8, 0.2, and 0.2 nM for human D2, D3, and 5-HT 1A, respectively). In vivo, SSR181507 inhibited [3H] raclopride binding to D2 receptors in the rat (1D50 = 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D2 antagonist and 5-HT1A agonist properties in the same concentration range in vitro (IC50 = 5.3 nM and EC50 = 2. 3 nM, respectively, in the GTPγS model) and in the same dose range in vivo (ED50 = 1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D2 receptor antagonism and 5-HT1A agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.