Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor

Abstract

(1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D1R, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of 2 for the development of D1R PAMs with superior allosteric properties.

Advances in clinical basic research: Performance, treatments, and mechanisms of Parkinson disease

“…The D2 class can stimulate cardiac, renal, mesenteric arteries, and sympathetic ganglia by stimulating adenylyl cyclase to produce camp, which promotes sodium efflux, renin secretion by juxtaglomerular cells, and finally adrenal and noradrenaline release. 55 , 56 Free radical damage, toxic effects of excitatory amino acids, calcium overload, and mitochondrial damage is associated with the degeneration of dopaminergic neurons. Neuroprotective therapy cuts off the damage chain reaction to prevent neuronal apoptosis and deterioration.…”

Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds

“…Further structural modification of these compounds may improve the performance of a specific biological activity [ 11 ]. Recent studies reported the action of some heterocycles against the Zika virus such as the already known chloroquine [ 12 ], sofosbuvir [ 13 ], ribavirin, and faviparivir [ 14 ], as well as new chemical entities, for example pyrrolo[2,3-d]pyrimidines [ 15 ]. A tremendous effort has been and is being invested in the development of effective molecules against ZIKV; however, there no approved anti-ZIKV drugs [ 16 ].…”

Synthesis, Single Crystal X-ray, Hirshfeld and DFT Studies of 1,8-Dichloro-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic Acid

“…Li et al reported on the synthesis and application of europium metal complexes containing an ethanoanthracene derivative as the binding ligand, which proved to have excellent water-quenching-resistant capability [21]. Another reperesntitive example reported by Lane and Capuano involved subsitituted ethanoanthracene, which worked effectively as an allosteric modulator of the dopamine D1 receptor [22].…”