Developing a novel treatment of cocaine use disorder using an IND dual inhibitor of Cav3 channel and soluble epoxide hydrolase - 7. PROJECT SUMMARY
Our SBIR Phase I proposal focuses on preclinical proof of concept studies on our IND AFA-281 for treatment
cocaine use disorder (CUD). AFA-281 is a new chemical entity discovered by AfaSci that inhibits both the T-type
Cav3 channels and soluble epoxide hydrolase (sEH). T-type channels consist of Cav3.1, 3.2, and 3.3 subunits.
Cocaine activates ion channels, including T-channels in the brain to increase neuronal excitability and alter
synaptic neurotransmission. Mibefradil, an old T-channel inhibitor blocks cocaine-induced GABAergic
abnormalities and hyperlocomotion in mice. Studies in Cav3.1 knockout mice revealed T-type channels play a
major role in sustaining ventral tegmental area neuronal excitability, and Cav3.2-deficient mice display reduced
psychostimulant sensitivity. Hence, two Cav3 subunits are biologically validated as CUD drug targets. Recent
studies suggest an involvement of neuroinflammation in addiction. Single sEH inhibitors or sEH genetic deletion
show a reduction in neuroinflammation. Although sEH involvement in CUD is unknown, we hypothesize our dual
inhibitor of Cav3/sEH could suppress cocaine-induced hyperexcitability and neuroinflammation, and thereby be
an effective treatment for CUD. The goal of this project is to test this feasibility.
This project’s innovation lies in AfaSci’s discovery of a series of patented dual modulators of Cav3 channels and
sEH with a favorable druggable profile. AfaSci completed lead identification through rational drug design, iterative
screenings using patch-clamp recordings and enzymatic assays. Lead optimization was conducted through 81
off-drug target selectivity screening and demonstrated no cardiac safety concerns using human cardiomyocytes
in vitro. Based on pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown an excellent
oral bioavailability (70% in rats and 92% in dogs), acceptable t1/2 (2.5-4.3 h), CNS penetration, broad analgesic
effects and good safety margins. Upon completion of the IND-enabling studies, AFA-281’s IND application was
recently accepted by the FDA for a primary indication in neuropathic pain. In Preliminary Studies, we have shown
cocaine-enhanced neural excitability was blocked by AFA-281 in rat thalamocortical slices. Rat cocaine-seeking
behavior indicated by self-administration (SA) of intravenous (IV) infusion of cocaine solution was suppressed
by AFA-281, and cocaine-elicited hyperlocomotion in rats and mice were restored to control levels by AFA-281.
Our Specific Aim 1 in this project is to rigorously investigate AFA-281’s effects on rat intentional drug seeking
via SA of IV infusion of cocaine in acquisition training and compulsive reward seeking under progress ratio
schedule and on reinstatement in relapse. Our Specific Aim 2 is to investigate PK/PD of AFA-281 for suppressing
cocaine seeking behavior and cocaine-induced hyperlocomotion in rats. Success in SBIR Phase I project will
demonstrate proof of concept, leading to clinical development of AFA-281 for a secondary indication in CUD with
an SBIR Phase II project and/or with third party support. Ultimately, AFA-281 as a safe, effective, and accessible
medication will mitigate CUD.
