Opioid Activity of Spinally Selective Analogues ofN-Naphthoyl-β-naltrexamine in HEK-293 Cells and Mice

Abstract

Using the selective mu-kappa agonist, NNTA 1, as the prototype ligand, a series of closely related naphthalene analogues were synthesized to study the chemical space around the naphthalene moiety in an effort to evaluate how receptor selectivity is affected by chemical modification. Nine analogues (2–10) of compound 1 were synthesized and tested on HEK-293 cells expressing homomeric and heteromeric opioid receptors, and in the mouse tail-flick assay. It was found that a small change in structure produces profound changes in selectivity in this series. This is exemplified by the discovery that introduction of a 6-fluoro group transforms 1 from a selective mu-kappa heteromeric receptor agonist to a delta-preferring agonist 7. The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance.

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

“…11 NNTA, where the aryl ring of β -naltrexamide is a bulky naphthalene, targets MOR–KOR heteromers and has poorer affinity for DOR-1, while 6′-fiuoro-NNTA is somewhat DOR-1 selective. 5a,34 A variety of selective MOR-1 antagonists based on 6 β -(4′-pyridyl)-naltrexamide (NAP) have also been reported. 6c,f While the SAR of naltrexamines has been extensively studied in the literature, only limited information is available on the pharmacology of 6-amido-7,8-didehydro-14- H -expoxymorphinans.…”

Structure–Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mice

“…Compound ( KAF2039-7 ) or vehicle was administered IT in a single injection 2 h before lights out ( t = 0 h). IT injections were performed as previously described. ,− Mouse body weight and food weight were recorded 2, 4, 6, 8, 24, 48, and 72 h postinjection following a single IT injection. Mice were given 7 days between treatments to re-establish pretreatment feeding behavior and body weight.…”

Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice

“…All experiments consisting of intracerebroventricular (ICV) and intrathecal (IT) injections were of crossover, non-fasting (nocturnal) feeding paradigm. Intrathecal injections were performed as previously described 16,22,23 . Desired compound or saline control was administered in one single injection via ICV/IT 2 hours before lights out (t=0h).…”