Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes

Animal studies indicate that the anxiolytic properties of the antipsychotic agent cyamemazine may result from blockade of serotonin 5-HT2C receptors and to a lesser extent from blockade of serotonin 5-HT3 receptors. Here, we used human recombinant receptors to determine the relative affinity of cyamemazine for serotonin and dopamine receptor subtypes. In addition, cyamemazine was tested in other brain receptor types and subtypes which are considered to mediate central nervous systems effects of drugs. Hence, cyamemazine affinity was determined in human recombinant receptors expressed in CHO cells (hD(2), hD(3), and hD(4.4) receptors, h5-HT1A, h5-HT2A, h5-H-TC, and h5-HT7, and hM(1), hM(2), hM(3), hM(4), and hM(5) receptors), L-cells (hD(1) receptor), and HEK-293 cells (h5-HT3 receptors) or natively present in N1E-115 cells (5-HT3 receptors) or in rat cerebral cortex (non-specific alpha(1)- and alpha(1)-adrenoceptors, GABA(A) and GABA(B) receptors, H-3 histamine receptors), and guinea-pig cerebellum (H-1 central and H-2 histamine receptors) membranes. Similarly to atypical antipsychotics, cyamemazine exhibited high affinity for: (i) h5-HT2A receptors (K-i = 1.5 +/- 0.7 nM, mean +/- SEM, N = 3) and this was four times higher than for hD(2) receptors (K-i = 5.8 +/- 0.8 nM), (ii) h5-HT2C receptors (K-i = 11.8 +/- 2.2 nM), and (iii) 5-HT7 receptors (K-i = 22 nM). Conversely, cyamemazine exhibited very low affinity for h5-HT3 receptors (K-i = 2.9 +/- 0.4 muM). In conclusion, similarly to atypical antipsychotic agents, cyamemazine, possesses high affinity for h5-HT2A, h5-HT2C, and h5-HT7 receptors, a feature which can explain its low propensity to cause extrapyramidal adverse reactions in clinical practice. The high affinity for h5-HT2C receptors, but not for h5-HT3 receptors, can account for the anxiolyfic activity of cyamemazine in human subjects. (C) 2002 Elsevier Science Inc. All rights reserved.