The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of 'Tail Wags Dog' Experiments

Autor: Sophia Kaska, Christine A. Herdman, Sergio A. Hassan, Thomas E. Prisinzano, Yong-Sok Lee, Sarah L. Withey, Saadet Inan, Martin W. Adler, Rachel Saylor Crowley, Meining Wang, Thomas C. Irvin, Jonathan L. Katz, Arthur E. Jacobson, Jack Bergman, Aaron M. Chadderdon, Theresa A. Kopajtic, Kenner C. Rice, John R. Traynor, Ellen B. Geller, Carol A. Paronis, Ramsey D. Hanna
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Agonist
forskolin-induced cAMP accumulation assays
TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES
Molecular model
molecular modeling & simulation
Stereochemistry
medicine.drug_class
Pharmaceutical Science
Stimulation
01 natural sciences
Partial agonist
Analytical Chemistry
lcsh:QD241-441
03 medical and health sciences
respiratory depression
lcsh:Organic chemistry
β-arrestin recruitment assays
Opioid Receptor Binding
TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY
Drug Discovery
medicine
Moiety
Physical and Theoretical Chemistry
Receptor
030304 developmental biology
0303 health sciences
010405 organic chemistry
Chemistry
Organic Chemistry
TheoryofComputation_GENERAL
(−)-N-phenethylnorhydromorphone analogs
0104 chemical sciences
MOR and DOR agonists
Opioid
Chemistry (miscellaneous)
opioid
Molecular Medicine
bifunctional ligands
[35S]GTPgammaS assay
medicine.drug
MathematicsofComputing_DISCRETEMATHEMATICS
bias factor
Zdroj: Molecules
Volume 25
Issue 11
Molecules, Vol 25, Iss 2640, p 2640 (2020)
ISSN: 1420-3049
DOI: 10.3390/molecules25112640
Popis: (&minus
)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTP&gamma
S binding, forskolin-induced cAMP accumulation assay, and MOR-mediated &beta
arrestin recruitment assays). &ldquo
Body&rdquo
and &ldquo
tail&rdquo
interactions with opioid receptors (a subset of Portoghese&rsquo
s message-address theory) were used for molecular modeling and simulations, where the &ldquo
address&rdquo
can be considered the &ldquo
body&rdquo
of the hydromorphone molecule and the &ldquo
message&rdquo
delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a &delta
/&mu
potency ratio of 1.2 in the ([35S]GTP&gamma
S) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje