Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

• Published in: Journal of medicinal chemistry 2014-08, Vol.57 (15), p.6383-6392
• Main Authors: Le Naour, Morgan, Lunzer, Mary M, Powers, Michael D, Kalyuzhny, Alexander E, Benneyworth, Michael A, Thomas, Mark J, Portoghese, Philip S
• Format: Article
• Language: English
• Subjects: Analgesics - adverse effects; Analgesics - chemistry; Analgesics - pharmacology; Animals; Arrestins - metabolism; Avoidance Learning - drug effects; beta-Arrestins; Calcium - metabolism; Drug Tolerance; HEK293 Cells; Humans; Indoles - adverse effects; Indoles - chemistry; Indoles - pharmacology; Mice; Naltrexone - adverse effects; Naltrexone - analogs & derivatives; Naltrexone - chemistry; Naltrexone - pharmacology; Protein Multimerization; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Stereoisomerism; Structure-Activity Relationship; Substance-Related Disorders - etiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500159d

It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3–10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.