TY - JOUR
T1 - 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
AU - Galaj, Ewa
AU - Bi, Guo Hua
AU - Klein, Benjamin
AU - Hempel, Briana
AU - Shaik, Anver Basha
AU - Gogarnoiu, Emma S.
AU - Friedman, Jacob
AU - Lam, Jenny
AU - Rais, Rana
AU - Reed, John F.
AU - Bloom, Shelley H.
AU - Swanson, Tracy L.
AU - Schmachtenberg, Jennifer L.
AU - Eshleman, Amy J.
AU - Janowsky, Aaron
AU - Xi, Zheng Xiong
AU - Newman, Amy Hauck
N1 - Funding Information:
AHN and ABS are inventors on an NIH patent that covers (S)- and (R)-ABS01-113. All rights are reserved by NIH. This research was supported by the National Institute on Drug Abuse Intramural Research Program (Z1A DA000424), U.S. DOJ/DEA [Interagency agreement D-15-OD-0002] (AJ), Department of Veterans Affairs Merit Review [I01BX002758] and Department of Veterans Affairs Award Senior Research Career Scientist programs [1IK6BX005754] (AJ), and NIH/NIDA [Interagency agreement ADA12013] (AJ). The contents do not represent the views of the U.S. Department of Veterans Affairs, U.S. Department of Justice, Drug Enforcement Administration, or the United States Government.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85136208312&partnerID=8YFLogxK
U2 - 10.1038/s41386-022-01379-1
DO - 10.1038/s41386-022-01379-1
M3 - Article
C2 - 35879349
AN - SCOPUS:85136208312
SN - 0893-133X
VL - 47
SP - 2309
EP - 2318
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 13
ER -