Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D 1 Receptor.

(1) Background: Two first-in-class racemic dopamine D ₁ receptor (D ₁ R) positive allosteric modulator (PAM) chemotypes ( 1 and 2 ) were identified from a high-throughput screen. In particular, due to its selectivity for the D ₁ R 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(3 H )-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D ₁ R, 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 D ₁ R PAMs with superior allosteric properties.