Deconstructing 14-phenylpropyloxymetopon: minimal requirements for binding to mu opioid receptors.
A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.
Dept. of Phar. Sci., Univ. of MD, School of Pharmacy, 20 N. Pine Street, Baltimore, MD 21201, USA.
Lidiya
L
Stavitskaya
Jihyun
J
Shim
Jason R
JR
Healy
Rae R
RR
Matsumoto
Alexander D
AD
MacKerell
Andrew
A
Coop
D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry*; D011485:Protein Binding; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*
C478565:14-phenylpropoxymetopon; D005021:Ethylamines; D009025:Morpholines; D017450:Receptors, Opioid, mu