Highly potent and selective zwitterionic agonists of the delta-opioid receptor. Part 1.
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.
Middleton
Donald S
DS
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. don.s.middleton@pfizer.com
Maw
Graham N
GN
Challenger
Clare
C
Jessiman
Alan
A
Johnson
Patrick S
PS
Million
William A
WA
Nichols
Carly L
CL
Price
Jenny A
JA
Trevethick
Michael
M
D000818:Animals; D004285:Dogs; D015195:Drug Design; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D008970:Molecular Weight; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013329:Structure-Activity Relationship
D007211:Indoles; D007546:Isoquinolines; D017465:Receptors, Opioid, delta