A highly D(3)R-selective and efficacious partial agonist (S)-ABS01-113 compared to its D(3)R-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder

The non-medical use of opioids has become a national crisis in the USA. Developing non-opioid pharmacotherapies for controlling this opioid epidemic is urgent. Dopamine D(3) receptor (D(3)R) antagonists and low efficacy partial agonists have shown promising profiles in animal models of opioid use disorders (OUD). However, to date, advancement to human studies has been limited. Here we report the effects of (S)- and (R)-enantiomers of (±)-ABS01-113, structural analogs of the D(3)R partial agonist, (±)-VK4-40, in which the 3-OH in the linking chain is replaced by 3-F group. (S)- and (R)-ABS01-113 are identical in chemical structure but with opposite chirality. In vitro receptor binding and functional assays indicate that (S)-ABS01-113 is an efficacious (55%) and potent (EC(50) = 7.6 ± 3.9 nM) D(3)R partial agonist, while the (R)-enantiomer is a potent D(3)R antagonist (IC(50) = 11.4 nM). Both (S)- and (R)-ABS01-113 bind with high affinity to D(3)R (K(i) = 0.84 ± 0.16 and 0.37 ± 0.06 nM, respectively); however, the (S)-enantiomer is more D(3)/D(2)-selective (>1000-fold). Pharmacokinetic analyses indicate that both enantiomers display excellent oral bioavailability and high brain penetration. Systemic administration of (S)- or (R)-ABS01-113 alone failed to alter open-field locomotion in male rats and mice. Interestingly, pretreatment with (S)- or (R)-ABS01-113 attenuated heroin-enhanced hyperactivity, heroin self-administration, and (heroin + cue)-induced reinstatement of drug-seeking behavior. Together, these findings reveal that both enantiomers, particularly the highly selective and efficacious D(3)R partial agonist (S)-ABS01-113, demonstrate promising translational potential for the treatment of OUD.