Dopamine D3/D2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

Anaerobic Hydroxylation of C(sp3)-H Bonds Enabled by the Synergistic Nature of Photoexcited Nitroarenes.

A photoexcited-nitroarene-mediated anaerobic C-H hydroxylation of aliphatic systems is reported. The success of this reaction is due to the bifunctional nature of the photoexcited nitroarene, which serves as the C-H bond activator and the oxygen atom source. Compared to previous methods, this approach is cost- and atom-economical due to the commercial availability of the nitroarene, the sole mediator of the reaction. Because of the anaerobic conditions of the transformation, a noteworthy expansion in substrate scope can be obtained compared to prior reports. Mechanistic studies support that the photoexcited nitroarenes engage in successive hydrogen atom transfer and radical recombination events with hydrocarbons, leading to N-arylhydroxylamine ether intermediates. Spontaneous fragmentation of these intermediates leads to the key oxygen atom transfer products.

Photoinduced Oxygen Transfer Using Nitroarenes for the Anaerobic Cleavage of Alkenes.

Herein we report the anaerobic cleavage of alkenes into carbonyl compounds using nitroarenes as oxygen transfer reagents under visible light. This approach serves as a safe and practical alternative to mainstream oxidative cleavage protocols, such as ozonolysis and the Lemieux-Johnson reaction. A wide range of alkenes possessing oxidatively sensitive functionalities underwent anaerobic cleavage to generate carbonyl derivatives with high efficiency and regioselectivity. Mechanistic studies support that the transformation occurs via direct photoexcitation of the nitroarene followed by a nonstereospecific radical cycloaddition event with alkenes. This leads to 1,3,2- and 1,4,2-dioxazolidine intermediates that fragment to give the carbonyl products. A combination of radical clock experiments and in situ photoNMR spectroscopy revealed the identities of the key radical species and the putative aryl dioxazolidine intermediates, respectively.

A highly D3R-selective and efficacious partial agonist (S)-ABS01-113 compared to its D3R-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 D3 receptor (D3R) 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 D3R 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 (EC50 = 7.6 ± 3.9 nM) D3R partial agonist, while the (R)-enantiomer is a potent D3R antagonist (IC50 = 11.4 nM). Both (S)- and (R)-ABS01-113 bind with high affinity to D3R (Ki = 0.84 ± 0.16 and 0.37 ± 0.06 nM, respectively); however, the (S)-enantiomer is more D3/D2-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 D3R partial agonist (S)-ABS01-113, demonstrate promising translational potential for the treatment of OUD.