Chemmedchem 2012-03-05

Selective agonists for dopamine/neurotensin receptor heterodimers.

Susanne Koschatzky, Peter Gmeiner

Index: ChemMedChem 7(3) , 509-14, (2012)

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Abstract

The neuromodulatory peptide neurotensin has been described to functionally interact with dopaminergic pathways of the human brain. We employed radioligand binding studies to investigate the physical interaction between co-expressed dopamine D(2L) or D₃ and neurotensin NTS₁ or NTS₂ receptors. Substantial cross-inhibitory effects of both receptor subtypes NTS(1) and NTS₂ on the agonist binding of D(2L) or D₃ were detected in the presence of neurotensin. To identify ligand-specific modulation and subtype-dependent differences, the novel dopamine receptor agonists 5 and 6 bearing the 7-OH-DPAT pharmacophore were synthesized. Exceptional ligand specificity was observed for D₃-NTS₂ co-expression, which gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of neurotensin. Comparing the binding properties of dopaminergic compounds in the presence of neurotensin, dopamine receptor subtype-selective profiles of the cross-inhibitory effect of neurotensin were observed.Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.