Discovery of mu-opioid selective ligands derived from 1-aminotetralin scaffolds made via metal-catalyzed ring-opening reactions.
A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).
Dockendorff
Chris
C
Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
Jin
Shujuan
S
Olsen
Madeline
M
Lautens
Mark
M
Coupal
Martin
M
Hodzic
Lejla
L
Spear
Nathan
N
Payza
Kemal
K
Walpole
Christopher
C
Tomaszewski
Mirosław J
MJ
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D008024:Ligands; D012238:Rhodium