A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers.
In view of recent pharmacological studies suggesting the existence of delta-kappa opioid receptor heterodimers/oligomers in the spinal cord, we have synthesized and evaluated (intrathecally in mice) a series of bivalent ligands (KDN series) containing kappa and delta antagonist pharmacophores. Pharmacological and binding data have provided evidence for the bridging of spinal delta-kappa receptor heterodimers by KDN-21 and for their identification as delta(1) and kappa(2). The selectivity profile of KDN-21 and the apparent absence of coupled delta(1)-kappa(2) phenotypes in the brain suggest a new approach for targeting receptors.
Bhushan
Rashmi G
RG
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Sharma
Shiv K
SK
Xie
Zhihua
Z
Daniels
David J
DJ
Portoghese
Philip S
PS
D000818:Animals; D002460:Cell Line; D006801:Humans; D008024:Ligands; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010641:Phenotype; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C487409:KDN 21; D008024:Ligands; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; C055382:naltrindole