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Differences in the Central Nervous System Distribution and Pharmacology of the Mouse 5-Hydroxytryptamine-6 Receptor Compared with Rat and Human Receptors Investigated by Radioligand Binding, Site-Directed Mutagenesis, and Molecular Modeling

Neurology and GI Centre of Excellence for Drug Discovery (W.D.H., B.A., A.R.C., L.A., A.D.M.), Computational, Analytical and Structural Sciences (F.E.B.), and Psychiatry Centre of Excellence for Drug Discovery (G.W.P.), GlaxoSmithKline, Harlow, Essex, United Kingdom

There is increasing evidence for a role of 5-hydroxytrypta-mine-6 (5-HT₆) receptors in cognitive function. In the rat and human brain, 5-HT₆ receptors are widely expressed and highly enriched in the basal ganglia. However, in the mouse brain, only very low levels of 5-HT₆ receptor mRNA and receptor protein, measured by TaqMan reverse transcriptase-polymerase chain reaction and selective radioligand binding, could be detected, with no evidence of enrichment in the basal ganglia. The mouse receptor was cloned and transiently expressed in human embryonic kidney 293 cells to characterize its pharmacological profile. Despite significant sequence homology between human, rat, and mouse 5-HT₆ receptors, the pharmacological profile of the mouse receptor was significantly different from the rat and human receptors. Four amino acid residues, conserved in rat and human and divergent in mouse receptors, were identified, and various mutant receptors were generated and their pharmacologies studied. Residues 188 (tyrosine in mouse, phenylalanine in rat and human) in transmembrane region 5 and 290 (serine in mouse, asparagine in rat and human) in transmembrane region 6 were identified as key amino acids responsible for the different pharmacological profiles. Molecular modeling of the receptor and docking of selective and nonselective compounds was undertaken to elucidate the ligand receptor interactions. The binding pocket was predicted to be different in the mouse compared with rat and human 5-HT₆ receptors, and the models were in excellent agreement with the observed mutation results and have been used extensively in the design of further selective 5-HT₆ antagonists.

Received June 26, 2003; accepted August 25, 2003.

Address correspondence to: Dr. Warren D. Hirst, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom. E-mail: Warren.D.Hirst{at}gsk.com

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