Synthesis and Preliminary Pharmacological Evaluation of 4′-Arylalkyl Analogues of Clozapine. IV.* The Effects of Aromaticity and Isosteric Replacement
Ben Capuano A B , Ian T. Crosby A , Edward J. Lloyd A , Anna Podloucka A and David A. Taylor AA Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Vic. 3052, Australia.
B Corresponding author. Email: ben.capuano@pharm.monash.edu.au
Australian Journal of Chemistry 61(12) 930-940 https://doi.org/10.1071/CH08307
Submitted: 18 July 2008 Accepted: 30 September 2008 Published: 10 December 2008
Abstract
We report the synthesis and preliminary pharmacological activity of a new series of tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. These compounds were designed based on a revised structural model, and investigate the length and nature of a designated linker (alkyl and alkyloxy) and the nature of the introduced aryl group (aromatic and heteroaromatic). The chemistry and structural characterization of this series of 4′-arylalkyl(oxy) analogues of clozapine are described. Preliminary results on the pharmacological effects of the selected linkers and introduced aryl groups on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. Psychosis-related animal behavioural data for promising compounds identified from the receptor binding screen are also presented.
Acknowledgements
The authors gratefully acknowledge Stuart Thomson for NMR and mass spectra of compounds described, and Kaitlyn Ky for her contribution to synthesis and pharmacological testing. Funding for the present work was provided by the Victorian College of Pharmacy (Monash University).
[1]
A. Jablensky,
N. Sartorius,
A. Korten,
G. Ernberg,
M. Anker,
J. E. Cooper,
J. R. Day,
Br. J. Psychiatry 1987, 151, 408.
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
| Crossref | GoogleScholarGoogle Scholar |
* Part III, Aust. J. Chem. 2007, 60, 928.
