SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Abstract

monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT 1A receptors (K I ¼ 0.8, 0.2, and 0.2 nM for human D 2 , D 3 , and 5-HT 1A , respectively). In vivo, SSR181507 inhibited [ 3 H]raclopride binding to D 2 receptors in the rat (ID 50 ¼ 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D 2 antagonist and 5-HT 1A agonist properties in the same concentration range in vitro (IC 50 ¼ 5.3 nM and EC 50 ¼ 2.3 nM, respectively, in the GTPgS model) and in the same dose range in vivo (ED 50 ¼ 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 D 2 receptor antagonism and 5-HT 1A 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.

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

“…A role for the D 2 receptor in assisting in this action cannot be excluded (Nakamura et al, 2006). Thus, data from the present electrophysiological and catalepsy studies, coupled with the results with 1192U90 and SSR181517 (Jones-Humble et al, 1996;Claustre et al, 2003), support the hypothesis of limbic selectivity with mixed serotonin 5-HT 1A agonists and D 2 antagonists in the same molecule.…”

“…Thus, based on its electrophysiological profile, SLV313 may be classified as an atypical antipsychotic preclinically. It is possible that SLV313-induced agonistic action at serotonin 5-HT 1A receptors may be important in producing its VTA-selective effects since the in vivo electrophysiological results obtained with SLV313 are similar to those reported following the chronic administration of the mixed D 2 antagonist/5-HT 1A receptor agonists 1192U90 and SSR181507 (Jones-Humble et al, 1996;Claustre et al, 2003). A role for the D 2 receptor in assisting in this action cannot be excluded (Nakamura et al, 2006).…”

“…Thus, aripiprazole appears devoid of intrinsic agonist actions at serotonin 5-HT 1A receptors in vivo using the paradigms described here. Interestingly, in vivo electrophysiological studies have demonstrated that ziprasidone and SSR181507 act as agonists at serotonin 5-HT 1A receptors and reduce dorsal raphe nucleus serotonergic cell firing (Sprouse et al, 1999;Claustre et al, 2003). Clozapine and olanzapine, however, appear to mediate this effect via a 1 noradrenergic receptors (Sprouse et al, 1999;Lejeune et al, 1994).…”

“…It has also been suggested that ACh may also be of pivotal importance for the cognitive symptoms of schizophrenia at the level of both the mPFCx and hippocampus and that atypical antipsychotics increase dopamine and ACh in both of these brain areas (Eichenbaum et al, 1999;Seidman et al, 2002;Moghaddam and Bunney, 1990;Kuroki et al, 1999;Ichikawa et al, 2002a, b;Shirazi-Southall et al, 2002;Li et al, 2004;Chung et al, 2004) via serotonin 5-HT 1A receptordependent mechanisms (Rollema et al, 1997;Ichikawa and Meltzer, 1999;Li et al, 2004). Recent studies with SSR181507 suggested that combined serotonin 5-HT 1A and dopamine D 2 antagonism, with the absence of serotonin 5-HT 2A receptor antagonism, augments dopamine levels in the mPFCx (Claustre et al, 2003). This serotonin 5-HT 1A -dependent increase in hippocampal dopamine was confirmed in the present study with SLV313.…”

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

“…These considerations have led to the development of compounds with preferential DA D 2 receptor antagonist or partial agonist, and 5-HT 1A agonist activities, such as bifeprunox (Feenstra et al, 2001;Wolf, 2003), SSR181507 (Claustre et al, 2003;Depoortere et al, 2003;Boulay et al, 2004), SLV313 McCreary et al, 2002), and sarizotan (that has been re-oriented towards an antidyskinetic indication: Bibbiani et al, 2001;Rabiner et al, 2002;Bartoszyk et al, 2004).…”