The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D₂Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat

Abstract

Hence, we evaluated in vivo D 2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (Ϫ)-OSU6162 and ACR16 showed robust dose-dependent striatal D 2 occupancy with ED 50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (Ϫ)-OSU6162 and 35 to 74% (10 -60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (Ϫ)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychoticlike effects, with low motor side effect liability, in a dose range that corresponds to high D 2 in vivo occupancy.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…First, pridopidine exhibits certain effects not typical of D2R antagonists, such as procognitive and prosocial effects (41). Second, pridopidine treatment does not elicit certain behaviors expected of D2R antagonists, such as catalepsy (42). Third, effects of pridopidine on certain behaviors associated with D2R antagonism, such as the dampening of amphetamine-induced hyperactivity, persist in D2R KO mice, in contrast to typical D2R antagonists, such as haloperidol (43).…”

The Tetrahydroisoquinoline Derivative SB269,652 Is an Allosteric Antagonist at Dopamine D3 and D2 Receptors

“…In general, allosteric modulators are well tolerated and can fine-tune pharmacological responses to endogenous neurotransmitters and exogenous agents, underpinning interest in their clinical application either alone or as adjunctive treatments (Christopoulos and Kenakin, 2002;May et al, 2007). Accordingly, (Ϫ)-OSU6162 displayed antipsychotic-like properties in rats in the absence of extrapyramidal motor effects and with little induction of dyskinesia (Tamminga and Carlsson, 2002;Natesan et al, 2006;Rung et al, 2008), and PLG potentiated the induction of contralateral rotation by L-DOPA in unilateral 6-hydroxydopamine lesioned rats without exacerbating the induction of dyskinesia (Ott et al, 1996). These observations support the notion that, in addition to orthosteric agents, positive and negative allosteric modulators at D 2 and/or D 3 receptors could be therapeutically useful agents, used either alone or as adjunctive therapy.…”

Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!

“…Other agents showing in vivo or in vitro partial D 2 -like receptor activity represent putative antipsychotics, e.g. bifeprunox [38], SSR181507 [39], sarizotan [40], RGH-188 [41], 3PPP [42], ACR16, OSU6162 [43]. Interestingly, the N-desmethylclozapine, the major metabolites of clozapine, is also a partial D 2 -like agonist.…”