Investigation of Novel Primary and Secondary Pharmacophores and 3‑Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D3 Receptor Antagonists and Partial Agonists
datasetposted on 2019-10-15, 18:33 authored by Anver Basha Shaik, Vivek Kumar, Alessandro Bonifazi, Adrian M. Guerrero, Sophie L. Cemaj, Alexandra Gadiano, Jenny Lam, Zheng-Xiong Xi, Rana Rais, Barbara S. Slusher, Amy Hauck Newman
Dopamine D3 receptors (D3R) play a critical role in neuropsychiatric conditions including substance use disorders (SUD). Recently, we reported a series of N-(3-hydroxy-4-(4-phenylpiperazin-1-yl)butyl)-1H-indole-2-carboxamide analogues as high affinity and selective D3R lead molecules for the treatment of opioid use disorders (OUD). Further optimization led to a series of analogues that replaced the 3-OH with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D3R binding affinity (Ki = 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were developed to give enantiopure R- and S-enantiomers of the four lead compounds. Off-target binding affinities, functional efficacies, and metabolic profiles revealed critical structural components for D3R selectivity as well as drug-like features required for development as pharmacotherapeutics.
0.756 nM3- Findole -2-carboxamide analoguesdrug-like featuresseriesD 3 Rsubstance use disordersPP3- OH9 bpharmacophoreD 3 R selectivityD 3 R binding affinitySUD3- F-compoundschiral HPLC methodsSecondary PharmacophoresD 2 ROff-target binding affinitiesK iOUDenantiopure RBitopic Dopamine D 3 Receptor AntagonistsSPPartial Agonists Dopamine D 3 receptorsenantioselective synthesisopioid use disorders