Functionally Selective Dopamine D₂/D₃Receptor 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.

Molecular Determinants of Biased Agonism at the Dopamine D2Receptor

“…15,17 By suggesting that the lipophilic appendages may account for the induction of preferential signaling by addressing particular residues of an extended binding site, we could demonstrate that structurally atypical dopaminergics comprising an enyne moiety and a lipophilic appendage including triazolylalkoxybenzene derivatives are able to discriminate between Gα o1 -and Gα i2 -mediated signaling at D 2L and D 2S receptors. 16 Interestingly, the crystal structure of the 5-HT 2B receptor in complex with the biased agonist ergotamine 20,21 revealed ligand-contacting residues in identical positions, as we suggested by docking studies of D 2 and the functionally selective dopaminergic agent (S)-1 ( Figure 1). This finding indicates the potential existence of conserved receptor microdomains that are responsible for ligand bias.…”

“…These results indicate an analogous binding pose as suggested for the enyne analogues of type 1 when the more potent isomer has to be assigned as (S)-1 due to a reversal of nomenclature exerted by the C,O exchange in the structure. 16 Substantial stereospecific binding was observed for the aminotetralines (R)-and (S)-4. Whereas (R)-configuration led to K i values of 18, 30, and 1.2 nM, (S)-4 exhibited subnanomolar K i values of 0.47, 0.54, and 0.21 nM for D 2L , D 2S , and D 3 , respectively.…”

“…Staudinger reduction of the azide facilitated amide coupling of the primary amine in the presence of TBTUactivated 4-(3-(1-butyl-1H-1,2,3-triazol-4-yl)propoxy)-3-methoxybenzoic acid. 16 Upon fluoride-mediated desilylation of the TMS-protecting group, the triazolylalkoxybenzene-substituted oxa-enyne (S)-2 was obtained. The synthesis of the enantiomeric test compound (R)-2 was conducted from (R)-glutamine following an identical reaction sequence.…”

Dopamine D3 receptor agonists as pharmacological tools

“…Later, the role of GRK2 and GRK3 for the non-G-protein dependent signaling pathway was pointed out, highlighting also the importance of IC3 and IC2 as interacting site for β-arrestins in D 3 receptor (Kim et al, 2005), supported by mutations studies on IC3 and IC2 (Lan et al, 2009a(Lan et al, , 2009b. D 3 receptor selective (partial) agonists with tetramethylene (butyl) linker and heteroaromatic or enyne moieties as agonist warhead group have been described as biased (partial) receptor agonist at D 2/3 receptors (Dörfler et al, 2008;Hiller et al, 2013;Möller et al, 2014;Tschammer et al, 2011b). Recently enantioselective D 3 ligands based on 5-aminotetrahydropyrazolopyridine with strong biased signaling properties to D 3 receptor were developed (Tschammer et al, 2011a).…”

1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

“…The D 2 model was developed previously, 45 whereas the 5-HT 2A model was generated by an analogous procedure using MODELLER 9v4 80 . Prior to docking, both receptors were submitted to energy minimization using the AMBER package 81 …”