Binding of 5H-Dibenzo[a,d]cycloheptene and Dibenz[b,f]oxepin Analogs of Clozapine to Dopamine and Serotonin Receptors

Abstract

Series of 5,11-dicarbo- and 11-carbo-5-oxy-10-(1-alkyl-1,2,3,6-tetrahydro-4 pyridinyl) analogues and a 11-carbo-5-oxy-10-(1-methyl-4-piperidinyl) analogue of the atypical antipsychotic agent clozapine were prepared and tested for binding to the dopamine D-2L and D-4 and serotonin S-2A and 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 as high as or higher than those of clozapine, indicating that neither the diazepine structure nor the piperazine ring present in clozapine is essential for high antidopamine activity and or for high dopamine D-4 selectivity (Ki for the dopamine D-2L receptor/Ki for the dopamine D-4 receptor). Increasing in the effective size of the alkyl substituent at the tertiary amine nitrogen atom in the 1,2,3,6-tetrahydro-4-pyridinyl moiety in the 5H-dibenzo[a,d]cycloheptene series reduces the affinity for the dopamine D-4 receptor, but in the dibenz[b,f]oxepin series, no significant change in binding affinity to the dopamine D-4 receptor was observed. Equal or slightly higher affinity for the serotonin S-2A and S-2C receptors was observed for the 10-(1-ethyl-1,2,3,6-tetrahydro-4- pyridinyl) analogues in both series, but for the 10-[1,2,3,6-tetrahydro-1-(2-propenyl)-4- pyridinyl] analogues, any favourable steric factor is overshadowed by an unfavorable electronic effect as a result of change in the basicity of the tertiary amino group in the pyridinyl moiety. Replacement of three of the four nitrogen atoms in clozapine with three carbon or two carbon atoms and an oxygen atom and removal of the chlorine atoms gives 10-(1,2,3,6-tetrahydro-1- methyl-4-pyridinyl)dibenzo[a,d]cycloheptene and 10-(1-methyl-4-piperidinyl)dibenz[b,f]oxepin, each having twice the binding activity to the dopamine D-4 receptor as does clozapine and a dopamine D-4 selectivity equal to that of clozapine.

New Short Strategy for the Synthesis of the Dibenz[b,f]oxepin Scaffold

“…The dibenz[ b , f ]oxepin scaffold is an important synthetic target because a large number of compounds having this skeleton present relevant biological activities; such as antidepressant [1], anxiolytic [2], antipsychotic [3,4], angiotensin-II-receptor-antagonist [5], and anti-inflammatory properties [6]. Additionally, a number of natural occurring dibenz[ b , f ]oxepins have been isolated from plants of the genus Bauhinia (fam.…”

Synthesis and Pharmacological Evaluation of Triflate-Substituted Analogues of Clozapine: Identification of a Novel Atypical Neuroleptic

“…16,19 An alternative approach to develop potential atypical neuroleptics is to slightly modify the basic 5H-dibenzo-[b,e] [1,4]diazepine skeleton of clozapine (1), to yield new chemical entities (NCEs), hopefully keeping the beneficial properties of clozapine (1) and losing some of the side-effects. [23][24][25] Among the newer antipsychotics that have emerged from this approach are olanzapine 26,27 and seroquel. 28 Interestingly, the binding profiles of these two compounds resemble that of clozapine (1) with some subtle differences.…”

Structure−Activity Relationships of a Series of Substituted Benzamides: Potent D2/5-HT2 Antagonists and 5-HT1a Agonists as Neuroleptic Agents

“…Of the several theories that have been advanced to explain clozapine's atypical antipsychotic profile, the mixed dopamine D 2 / serotonin 5-HT 2 hypothesis has been the subject of most recent investigations. [8][9][10][11][12][13][14][15][16][17][18][19] For example, compounds such as risperidone, 9 ocaperidone, 10 sertindole, 11 and ziprasidone 12 are mixed D 2 /5-HT 2 antagonists at various stages of investigation.…”