and Objectives: Clozapine (CLOZ) and levomepromazine (LMP) improve treatment-resistant schizophrenia. The superior efficacy of CLOZ compared with other antipsychotic agents has been attributed to an effect on D1-like and D4 receptors. We examined the binding of LMP, CLOZ and cyamemazine (CMZ), a neuroleptic analog of LMP, to human recombinant dopamine (rDA) receptor subtypes. Methods: Binding studies were performed on frozen membrane suspensions of human rDA receptor subtypes expressed in Sf9

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... expressed in Sf9 cells. Results: (i) LMP has a high affinity (Ki, nM) for rD2 receptor subtypes (rD2L 8.6; rD2S 4.3; rD3 8.3; rD4.2 7.9); (ii) LMP and CLOZ have comparable affinities for the rD1 receptor (54.3 vs 34.6); (iii) CMZ has high affinities for rD2-like and rD1-like receptors (rD2L 4.6; rD2S 3.3; rD3 6.2; rD4.2 8.5; rD1 3.9; rD5 10.7); (iv) CMZ is 9 times more potent than CLOZ at the rD1 receptor and 5 times more potent than CLOZ at the rD4.2 receptor; (v) CMZ has high affinities for rD1 and rD5 receptor subtypes compared with LMP and CLOZ. Conclusions: If D1 and D4 receptors are important sites for the unique action of CLOZ, the present study points to a need for clinical trials comparing CMZ with CLOZ in schizophrenia and in particular, treatment-resistant schizophrenia, especially given the risk for agranulocytosis with CLOZ.