Selective agonists for dopamine/neurotensin receptor heterodimers.
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.
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstr. 19, 91052 Erlangen, Germany.
Susanne
S
Koschatzky
Peter
P
Gmeiner
D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009496:Neurotensin / Q000494:pharmacology; D011869:Radioligand Assay; D020239:Receptor Cross-Talk; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014162:Transfection
D018491:Dopamine Agonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D018028:Receptors, Neurotensin; D013764:Tetrahydronaphthalenes; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C031349:7-hydroxy-2-N,N-dipropylaminotetralin