title: Functionally selective dopamine D2/D3 receptor agonists comprising an enyne moiety.
abstract: Dopaminergics of types 1 and 2 incorporating a conjugated enyne as an atypical catechol-simulating moiety were synthesized in enantiomerically pure form and investigated for their metabolic stability. Radioligand binding studies indicated high affinity to D2-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D(2L)- and D(2S)-mediated [(35)S]GTPγS incorporation in the presence of coexpressed Gα(o) and Gα(i) subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D(2S)-promoted G(o) activation over G(i) coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for G(o) activation than for G(i) coupling at the D(2L) subtype. Functional selectivity for β-arrestin recruitment over G(i) activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred β-arrestin recruitment compared to G(o) coupling.
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hiller
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.forename: Frank W
authors.initials: FW
authors.lastname: Heinemann
authors.forename: Karsten
authors.initials: K
authors.lastname: Meyer
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000480:Alkynes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D018491:Dopamine Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000475:Alkenes; D000480:Alkynes; D018491:Dopamine Agonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3