Synthesis of allosteric molecules for DOR-KOR heteromer-mediated peripheral analgesia

Our goal in this highly collaborative project is to develop compounds to selectively activate the delta opioid receptor (DOR)-kappa opioid receptor (KOR) heteromer allosterically. to promote antinociception effects in vivo and advance lead compounds as possible therapies for pain.Our approach will focus on a DOR/KOR heteromer characteristic known as ???interprotomer allosterism???. wherein an orthosteric ligand for one of the protomers can allosterically alter the binding and/or function of an orthosteric ligand for the second protomer.
 Our UTSA synthesis and medicinal chemistry aim will focus on preparing analogs of three different chemical series of known DOR and KOR ligands highlighted in the grant.As leads are identified from both the in silico and de novo design approaches. medicinal chemistry studies will look to optimize DOR/KOR activity and peripherally-restricted physicochemical properties through an iterative process.All compounds prepared in the McHardy lab at UTSA will be fully characterized by 1H and 13C NMR. and HPLC/MS. targeting a chemical purity of >97% and will be registered in the CIDD compound file. and assigned a CIDD identification number.Small retains (2-5 mg) will be held at the CIDD medicinal chemistry core facility and 5-10 mg of each compound will be sent to Dr. Clark???s lab for in vitro DOR/KOR assessment.