Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity.
Some kappa opioid receptor agonists of the arylacetamide class, for example, ICI 199441 (1), were found to strongly inhibit the activity of cytochrome P450 2D6 (CYP2D6) (1: CYP2D6 IC50=26 nM). Certain analogs bearing a substituted sulfonylamino group, for example, 13, were discovered to have significantly reduced CYP2D6 inhibitory activity (13: CYP2D6 IC50>10 microM) while displaying high affinity toward the cloned human kappa opioid receptor, good kappa/delta and kappa/mu selectivity, and potent in vitro and in vivo agonist activity.
Le Bourdonnec
Bertrand
B
Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. blebourdonnec@adolor.com
Ajello
Christopher W
CW
Seida
Pamela R
PR
Susnow
Roberta G
RG
Cassel
Joel A
JA
Belanger
Serge
S
Stabley
Gabriel J
GJ
DeHaven
Robert N
RN
DeHaven-Hudkins
Diane L
DL
Dolle
Roland E
RE
D000081:Acetamides / Q000494:pharmacology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013379:Substrate Specificity
D000081:Acetamides; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D017473:Receptors, Opioid, kappa; C030686:acetamide