Azepinone as a conformational constraint in the design of kappa-opioid receptor agonists.
A new class of kappa-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide kappa agonist 1, ICI 199441. The most active compound identified was ligand 4a (K(i)=0.34 nM), which demonstrated potent antinociceptive activity after oral administration in rodents.
Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA.
Paul A
PA
Tuthill
Pamela R
PR
Seida
William
W
Barker
Joel A
JA
Cassel
Serge
S
Belanger
Robert N
RN
DeHaven
Michael
M
Koblish
Susan L
SL
Gottshall
Patrick J
PJ
Little
Diane L
DL
DeHaven-Hudkins
Roland E
RE
Dolle
D019342:Acetic Acid / Q000737:chemistry; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D005557:Formaldehyde / Q000737:chemistry; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001381:Azepines; D008024:Ligands; D017473:Receptors, Opioid, kappa; D005557:Formaldehyde; D019342:Acetic Acid