Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D₃ (D₃R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.

@article{pmid37467430,

title = {Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D_{3} (D_{3}R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics},

author = {Alessandro Bonifazi and Elizabeth Saab and Julie Sanchez and Antonina L Nazarova and Saheem A Zaidi and Khorshada Jahan and Vsevolod Katritch and Meritxell Canals and J Robert Lane and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/37467430/},

doi = {10.1021/acs.jmedchem.3c00417},

issn = {1520-4804},

year  = {2023},

date = {2023-08-01},

urldate = {2023-08-01},

journal = {J Med Chem},

volume = {66},

number = {15},

pages = {10304--10341},

abstract = {A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and DR, respectively, improving the dopamine receptor subtype selectivity (e.g., DR over DR) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted -(2,4)-pyrrolidine and -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists  () or loperamide (). The lead compounds , ,  and  have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via DR antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}