kappa Opioid receptor selective affinity labels: electrophilic benzeneacetamides as kappa-selective opioid antagonists.
2-(3,4-Dichlorophenyl)-N-methyl-N-[1-(3- or 4-substituted phenyl)-2-(1-pyrrolidinyl)ethyl]-acetamides 3-6 were synthesized as kappa-selective affinity labels and evaluated for opioid activity. In smooth muscle preparations, the non-electrophilic parent compound (+)-S-2 and the affinity labels 3-6 behaved as kappa agonists in that they were potently antagonized by norbinaltorphimine (norBNI). In addition to the high binding affinity and selectivity of the 3-isothiocyanate 3 (DIPPA) to kappa opioid receptors, wash studies have suggested that this involves covalent binding. In the mouse tail-flick assay, the 3- and 4-substituted isomers (3 and 5, respectively) produced long-lasting antagonism of the antinociceptive effect of the kappa opioid agonist, (+/-)-trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]acetamide ((+/-)-U50,488). In contrast, the non-electrophilic parent compound (+)-S-2 and the fumaramate derivative 4 were devoid of antagonist activity in the tail-flick assay. At substantially different doses, DIPPA (3) and the 4-isothiocyanate 5 also produced antinociception in the mouse abdominal stretch assay. In addition, DIPPA and the 3-fumaramate methyl ester 4 had improved in vivo kappa-selectivities compared to the unsubstituted parent compound (+)-S-2 and the para-substituted derivative 5. The improved kappa-selectivities of 3 and 4 and the different agonist and antagonist potencies of 3 and 5 may be explained respectively by the existence of multiple kappa agonist binding sites and distinct agonist and antagonist binding sites. In view of the antagonist selectivity and the apparent irreversible binding of DIPPA to kappa receptors, it may serve as a useful pharmacologic or biochemical tool to investigate kappa opioid receptors.
Chang
A C
AC
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Takemori
A E
AE
Ojala
W H
WH
Gleason
W B
WB
Portoghese
P S
PS
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000345:Affinity Labels / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D011759:Pyrrolidines / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000345:Affinity Labels; D000700:Analgesics; D017879:Isothiocyanates; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C087549:2-(3,4-dichlorophenyl)-N-methyl-N-(1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl)acetamide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer