Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics
Graphical abstract
New multiple target drugs based on marketed neuroleptics have been designed, prepared and profiled maintaining dopamine hD2/hD3 receptor affinities, reducing histamine hH1 receptor affinities and introducing high affinity at histamine hH3 receptors (H3R). hD1/hD5 binding was heterogeneously shifted. The addition of an H3R pharmacophore to different typical and atypical neuroleptics by amide, amine or ester linkages resulted in a new profile of potential antipsychotics with low nanomolar to subnanomolar H3R affinities.
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Acknowledgments
We thank Prof. R. Leurs (Amsterdam), Prof. J. Shine (Sydney), Dr. P. Sokoloff (Paris), and Prof. J. Lehmann (Jena) for providing cell lines expressing the histamine H1 receptor and dopamine D2S, D3 and D1, D5 receptors, respectively. We thank C. Hertzsch for the preparation of 10 and 11.
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