BINDING OF 5H-DIBENZO[A,D]CYCLOHEPTENE AND DIBENZ[B,F]OXEPIN ANALOGS OF CLOZAPINE TO DOPAMINE AND SEROTONIN RECEPTORS

Series of 5,11-dicarbo- and -5-oxy-10-(1-alkyl-1,2,3,6-tetrahydro-4-py ridinyl) analogues and a 11-carbo-5-oxy-10-(1-methyl-4-piperidinyl) an alogue of the atypical antipsychotic agent clozapine were prepared and tested for binding to the dopamine D-2L and D-4 and serotonin S-2A an d S-2C receptors. Some of these analogues were found to have dopamine D-2L and D-4 and serotonin S-2A and S-2C receptor binding activities a s high as or higher than those of clozapine, indicating that neither t he diazepine structure nor the piperazine ring present in clozapine is essential for high antidopamine activity and or for high dopamine D-4 selectivity (K-i for the dopamine D-2L receptor/K-i for the dopamine D-4 receptor). Increasing in the effective size of the alkyl substitue nt at the tertiary amine nitrogen atom in the 1,2,3,6-tetrahydro-4-pyr idinyl moiety in the 5H-dibenzo[a,d]cycloheptene series reduces the af finity for the dopamine D-4 receptor, but in the dibenz[b,f]oxepin ser ies, no significant change in binding affinity to the dopamine D-4 rec eptor was observed. Equal or slightly higher affinity for the serotoni n S-2A and S-2C receptors was observed for the 10-(1-ethyl-1,2,3,6-tet rahydro-4-pyridinyl) analogues in both series, but for the 10-[1,2,3,6 -tetrahydro-1-(2-propenyl)-4-pyridinyl] analogues, any favorable steri c factor is overshadowed by an unfavorable electronic effect as a resu lt of change in the basicity of the tertiary amino group in the pyridi nyl moiety. Replacement of three of the four nitrogen atoms in clozapi ne with three carbon or two carbon atoms and an oxygen atom and remova l of the chlorine atoms gives ydro-1-methyl-4-pyridinyl)dibenzo[a,d]cy cloheptene and 10-(1-methyl-4-piperidinyl)dibenz[b,f]oxepin, each havi ng twice the binding activity to the dopamine D-4 receptor as does clo zapine and a dopamine D-4 selectivity equal to that of clozapine.