Effect of the amisulpride isomers on rat catalepsy.
The substituted benzamide amisulpride is currently administered in its racemic form. In the present study, the biochemical and cataleptogenic profiles of the two enantiomers (R+ and S-) were compared with those of the racemic mixture. Displacement binding studies showed that the (S-)-isomer possesses an higher affinity for dopamine D2-like receptor (K(i) 5.2+/-0.4 nM) compared to (R+)-amisulpride (K(i) 244+/-12 nM) and to (RS)-amisulpride (K(i) 9.8+/-0.8 nM). In contrast, (S-)-amisulpride binds the alpha(2)-receptor with an affinity (K(i) 1528+/-45 nM) lower than that of the (R+)-isomer (K(i) 375+/-34 nM) and of (RS)-amisulpride (K(i) 783+/-27 nM). The bar test was used to evaluate the catalepsy induced by each drug. (RS)-amisulpride induced catalepsy only at very high doses (>100 mg/kg, s.c.) whereas, (S-)-amisulpride produced a catalepsy at a lower dose (30 mg/kg, s.c.) and (R+)-amisulpride did not produce any catalepsy up to the dose of 75 mg/kg. Interestingly, (R+)-amisulpride reduced the catalepsy induced by (S-)-amisulpride (50 mg/kg, s.c.) or haloperidol (0.3 mg/kg, s.c.), at the doses of 50 or 30 mg/kg, respectively. These results indicate that the weak cataleptic properties of (RS)-amisulpride might partially rely on its (R+)-isomer and provide a further explanation for the atypical properties of amisulpride as an antipsychotic.
Marchese
Giorgio
G
Neuroscienze S.c.a.r.l., C.N.R., Cagliari, Italy.
Bartholini
Francesco
F
Ruiu
Stefania
S
Casti
Paola
P
Saba
Pierluigi
P
Gessa
Gian
G
Pani
Luca
L
D000077582:Amisulpride; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*
D017448:Receptors, Dopamine D2; D013469:Sulpiride; D000077582:Amisulpride