Use of receptor chimeras to identify small molecules with high affinity for the dynorphin A binding domain of the kappa opioid receptor.
A series of 2-substituted sulfamoyl arylacetamides of general structure 2 were prepared as potent kappa opioid receptor agonists and the affinities of these compounds for opioid and chimeric receptors were compared with those of dynorphin A. Compounds 2e and 2i were identified as non-peptide small molecules that bound to chimeras 3 and 4 with high affinities similar to dynorphin A, resulting in K(i) values of 1.5 and 1.2 nM and 1.3 and 2.2 nM, respectively.
Kumar
Virendra
V
Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. vkumar@adolor.com
Guo
Deqi
D
Marella
Michael
M
Cassel
Joel A
JA
Dehaven
Robert N
RN
Daubert
Jeffrey D
JD
Mansson
Erik
E
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004399:Dynorphins / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D008970:Molecular Weight; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D017473:Receptors, Opioid, kappa; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D004399:Dynorphins