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

Abstract

3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-Hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

“…8,9 The intensity was set to achieve a baseline between 2 and 3 s. Baseline latencies were determined before experimental treatments for all mice. Tail flick antinociception was assessed quantally as a doubling or greater of the baseline latency, with a maximal 10 s latency to minimize damage to the tail.…”

“…8 The amount of time subjects spent in each of three compartments was measured over a 30 min testing period. Prior to place conditioning, the animals ( n = 95) did not demonstrate significant differences in their time spent exploring the left (543 ± 13 s) vs right (571 ± 12 s) compartments ( p = 0.15; Student’s t -test), resulting in a combined preconditioning response of −0.1 ± 19 s. During each of the next 2 days, mice were administered vehicle (0.9% saline) and consistently confined in a randomly assigned outer compartment for 40 min, half of each group in the right chamber, half in the left chamber.…”

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

“…Mice were conditioned to drugs or vehicle as described previously (Varadi, Marrone, et al, ) with two modifications: (a) conditioning sessions lasted 40 min rather than 30 min and (b) a two‐chamber apparatus rather than a three‐chamber set‐up was utilized. One chamber contained a wire mesh floor and horizontal black/white striped wallpaper, whereas the second chamber contained a metal rod floor and vertical black/white striped wallpaper.…”

“…Mice were conditioned to drugs or vehicle as described previously (Varadi, Marrone, et al, 2015) with two modifications:…”

The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

“…Development of KOPr agonists with fewer side-effects (Law et al, 2013; Zhang et al, 2015) and reduced abuse potential (Morani et al, 2009) have recently received increased attention (Kivell and Prisinzano, 2010; Tsukahara-Ohsumi et al, 2011; Váradi et al, 2015; White et al, 2015). The recent clinical success of the potent KOPr agonist nalfurafine (Seki et al, 1999; Kumagai et al, 2010) illustrates the clinical utility of KOPr agonists for the management of pain and pruritus.…”