Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

doi:10.1016/j.bmcl.2008.09.012

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 2, 15 January 2009, Pages 538-542

https://doi.org/10.1016/j.bmcl.2008.09.012 Get rights and content

Abstract

Histamine H₃ receptor (H₃R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional histamine H₃ pharmacophore. The 4-(3-piperidinopropoxy)phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift affinity at dopamine D₂-like receptors (D₂ and D₃), to decrease affinity at histamine H₁ receptors, and to obtain H₃R ligands with low nanomolar or subnanomolar affinity. Change of effects at D₁-like receptors (D₁ and D₅) were heterogeneous. With these newly profiled compounds different antipsychotic properties might be achieved.

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.

Section snippets

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 D_2S, D₃ and D₁, D₅ receptors, respectively. We thank C. Hertzsch for the preparation of 10 and 11.

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Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

Abstract

Graphical abstract

Section snippets

Acknowledgments

Pharmacol. Ther.

J. Neurochem.

Drug Discov. Today

Bioorg. Med. Chem. Lett.

J. Org. Chem.

Br. J. Pharmacol.

Arch. Pharm. Pharm. Med. Chem.

Annu. Rev. Neurosci.

Schizophr. Bull.

Curr. Opin. Psychiatry

J. Med. Chem.

Br. J. Pharmacol.

Drug News Perspect.

Potential utility of histamine H₃ receptor antagonist pharmacophore in antipsychotics