Synthesis and Preliminary Pharmacological Evaluation of 4′-Arylalkyl Analogues of Clozapine. III. Replacement of the Tricyclic Nucleus with a Bicyclic Template
Ben Capuano A C , Ian T. Crosby A , Edward J. Lloyd A and David A. Taylor BA Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
B Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville VIC 3052, Australia.
C Corresponding author. Email: ben.capuano@vcp.monash.edu.au
Australian Journal of Chemistry 60(12) 928-933 https://doi.org/10.1071/CH07201
Submitted: 14 June 2007 Accepted: 15 August 2007 Published: 4 December 2007
Abstract
As a continuing part of our research program in search of novel compounds for the treatment of schizophrenia, we report the synthesis and preliminary receptor binding affinity for a series of bicyclic analogues of clozapine derived from a selection of promising tricyclic candidates published previously. These bicyclic compounds investigate some substituent effects and the length and nature of the linker between an ionizable nitrogen atom at physiological pH and the introduced aryl moiety. The chemistry, structural characterization, and in vitro evaluation are described. Preliminary findings on the effects on activity of the nature and length of the linker, degree of unsaturation, and selected substituents coupled to the bicyclic nucleus are discussed in relation to affinity for dopamine D4 and serotonin 5-HT2A receptors.
Acknowledgements
The authors gratefully acknowledge W. Lau for the in vitro pharmacology testing and S. Thomson for NMR and mass spectra of compounds described. Funding for this work was provided by Monash University (Parkville campus).
[1]
B. Capuano,
I. T. Crosby,
E. J. Lloyd,
D. A. Taylor,
Aust. J. Chem. 2002, 55, 565.
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