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New hybrids of clozapine and haloperidol and their isosteric analogues: synthesis, X-ray crystallography, conformational analysis and preliminary pharmacological evaluation

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Abstract

Schizophrenia is a debilitating mental disorder which affects approximately 1% of the world’s population. Clozapine is an atypical antipsychotic showing unmatched effectiveness in the control of treatment-resistant schizophrenia. Unlike typical antipsychotics, clozapine does not induce extrapyramidal side effects (EPS), tardive dyskinesia or elevate prolactin levels. However, clozapine can induce a potentially fatal blood disorder, agranulocytosis, in 1–2% of patients, severely limiting its clinical use. The model for antipsychotic activity under investigation is based on obtaining a clozapine-like profile with preferential dopamine D4 and serotonin 5-HT2A receptor affinity. Profiled herein are three unique members of a series of prospective antipsychotic agents. Compound (I) originated from the structural hybridization of the commercial therapeutics, clozapine and haloperidol, whilst compounds (II) and (III) possess an alternative tricyclic nucleus derived from JL13; a clozapine-like atypical antipsychotic developed by Liégeois et al. These compounds have been synthesized and characterized by means of elemental analysis, IR, 1H and 13C-NMR spectroscopy, MS and X-ray diffraction. Compound (I) crystallizes in space group P(−1) with a = 10.5032(1), b = 10.6261(2), c = 12.6214(3) Å, α = 81.432(1)°, β = 83.292(1)°, γ = 61.604(1)°, Z = 2, V = 1223.62(4) Å3, C28H29ClN4O, M r = 473.00, D c = 1.284 Mg/m3, μ = 0.185 mm−1, F(000) = 500, R = 0.0506 and wR = 0.1304. Compound (II) crystallizes in the monoclinic space group P21/c with a = 10.8212(2), b = 9.3592(2), c = 22.9494(5) Å, β = 106.471(1)°, Z = 4, V = 2228.88(8) Å3, C25H25ClN4O2, M r = 448.94, D c = 1.338 Mg/m3, μ = 0.202 mm−1, F(000) = 944, R = 0.0529 and wR = 0.1129. Compound (III) crystallizes in the monoclinic space group P21/c with a = 10.5174(2), b = 9.3112(2), c = 24.2949(5) Å, β = 98.666(1)°, Z = 4, V = 2352.03(8) Å3, C25H24Cl2N4O2, M r = 483.38, D c = 1.365 Mg/m3, μ = 0.306 mm−1, F(000) = 1008, R = 0.0478 and wR = 0.1067. The solid state conformations of (I), (II) and (III) exhibit the characteristic V-shaped buckled nature of the respective dibenzodiazepine and pyridobenzoxazepine nuclei with the central seven-membered heterocycle in a boat conformation. The molecules of (I) form a head-to-tail dimeric motif stabilized by hydrogen bonding. The results of a conformational analysis of compounds (I)–(III) investigating the effect of environment (in vacuo and aqueous solution) are presented. These analogues were tested for in vitro affinity for the dopamine D4 and serotonin 5-HT2A receptors and their comparative receptor binding profiles to clozapine and JL13 are reported.

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Acknowledgements

We gratefully acknowledge financial support from Monash University, Australia (VCP Small Grants Scheme #3652166).

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Authors and Affiliations

  1. Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, 3052, Australia

    Ben Capuano, Ian T. Crosby, Fiona M. McRobb, Vladimir V. Moudretski, David A. Taylor, Amelia Vom & Elizabeth Yuriev

  2. School of Chemistry, Monash University, Wellington Road, Clayton, VIC, 3800, Australia

    Craig M. Forsyth

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  1. Ben Capuano
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  2. Ian T. Crosby
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Correspondence to Ben Capuano.

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Capuano, B., Crosby, I.T., Forsyth, C.M. et al. New hybrids of clozapine and haloperidol and their isosteric analogues: synthesis, X-ray crystallography, conformational analysis and preliminary pharmacological evaluation. Struct Chem 21, 613–628 (2010). https://doi.org/10.1007/s11224-010-9591-0

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