Sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
Sterically hindered 5,11-dicarbo analogues of clozapine were prepared as potential chiral antipsychotic agents, with the possibility that for a particular analogue the antipsychotic activity of clozapine may reside in one enantiomer of the analogue whereas other unwanted biological effects of clozapine may be caused by the other enantiomer. Variable-temperature proton nuclear magnetic resonance studies showed that although 5-methylene-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene exists at room temperature as configurational enantiomers, the activation energy for thermal racemization is 19 kcal mol-1 at 105 degrees C, and it is doubtful that the enantiomers of this analogue can be isolated under usual laboratory conditions. The (Z)-5-ethylidene and 5-isopropylidene analogues have activation energies greater than 23 kcal mol-1 at 160 degrees C, and thus there is a possibility that the analogues can be obtained as their respective enantiomers. 5-Methyl-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene incorporates a chiral center which is not thermally racemized, but it exists at room temperature as two diasteromers with an activation energy for inversion of the 5H-dibenzo[a,d]cycloheptene ring of 21 kcal mol-1. When the 5,11-dicarbo analogues were tested in vitro for biological activity and their activities were compared to that of clozapine, the affinities for muscarinic and dopamine D-1 and D-2 sites were reduced but were still substantial. Thus the respective biological activities of the racemates indicate that the biological activities of the thermally stable enantiomers may be of importance in finding a clozapine derivative with fewer side effects than those shown by clozapine itself. Because of the susceptibility of the enamines to acid-catalyzed hydrolysis, resolution into respective enantiomers is not anticipated.
Rupard
J H
JH
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
de Paulis
T
T
Janowsky
A
A
Smith
H E
HE
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D002540:Cerebral Cortex / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D003984:Dibenzazepines / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D003984:Dibenzazepines; D007202:Indicators and Reagents; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D003024:Clozapine