GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.
Excellent chemoselectivity for intramolecular allylic C-H amination versus C]C aziridination was achieved through Co(II)-based metalloradical catalysis. Metalloradical catalyst [Co(P1)], the cobalt(II) complex of D 2h -symmetric porphyrin 3,5-Di t Bu-IbuPhyrin, was shown to be highly effective for selective intramolecular allylic C-H amination of both N-bishomoallylic and N-allylic sulfamoyl azides. The Co(II)-catalyzed intramolecular 1,6-C-H amination of these azides provides a general and efficient method to access the synthetically useful allylic 1,3-diamines under neutral and non-oxidative conditions, without complication from the competitive olefin aziridination. The origin of this remarkable chemoselectivity has direct relevance to the radical mechanism of Co(II)-based metalloradical amination.
Both arylsulfonyl and alkylsulfonyl azides can be effectively activated by the cobalt(II) complexes of D 2symmetric chiral amidoporphyrins for enantioselective radical 1,5-C−H amination to stereoselectively construct 5-membered cyclic sulfonamides. In addition to C−H bonds with varied electronic properties, the Co(II)-based metalloradical system features chemoselective amination of allylic C−H bonds and is compatible with heteroaryl groups, producing functionalized 5membered chiral cyclic sulfonamides in high yields with high enantioselectivities. The unique profile of reactivity and selectivity of the Co(II)-catalyzed C−H amination is attributed to its underlying stepwise radical mechanism, which is supported by several lines of experimental evidence.
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