Use of receptor chimeras to identify small molecules with high affinity for the dynorphin A binding domain of the kappa opioid receptor

Virendra Kumar; Deqi Guo; Michael Marella; Joel A Cassel; Robert N Dehaven; Jeffrey D Daubert; Erik Mansson

doi:10.1016/j.bmcl.2007.11.116

Use of receptor chimeras to identify small molecules with high affinity for the dynorphin A binding domain of the kappa opioid receptor

Bioorg Med Chem Lett. 2008 Jun 15;18(12):3667-71. doi: 10.1016/j.bmcl.2007.11.116. Epub 2007 Dec 4.

Authors

Virendra Kumar¹, Deqi Guo, Michael Marella, Joel A Cassel, Robert N Dehaven, Jeffrey D Daubert, Erik Mansson

Affiliation

¹ Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. vkumar@adolor.com

PMID: 18487043
DOI: 10.1016/j.bmcl.2007.11.116

Abstract

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.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Binding Sites / drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Dynorphins / chemistry
Dynorphins / pharmacology*
Molecular Structure
Molecular Weight
Receptors, Opioid, kappa / agonists*
Receptors, Opioid, kappa / chemistry
Receptors, Opioid, kappa / genetics
Recombinant Fusion Proteins / agonists*
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Small Molecule Libraries
Stereoisomerism
Structure-Activity Relationship

Substances

Acetamides
Receptors, Opioid, kappa
Recombinant Fusion Proteins
Small Molecule Libraries
Dynorphins