Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

Abstract

We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [35S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.

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

“…7–9,80 Binding was performed at 25 °C for 90 min. Binding in MOR-1/CHO was carried out in 50 mM potassium phosphate buffer with 5 mM MgSO 4 and 20 μ g/mL protein, while binding in KOR-1/CHO and DOR-1/CHO was carried out in 50 mM potassium phosphate pH = 7.0 buffer and 40 μ g/mL protein.…”

“…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.…”

“…Many approaches have been taken over the years, starting with the development of partial agonists or mixed agonist/antagonists. 5–9 A more recent approach takes advantage of biased agonism, in which distinct downstream signaling pathways are activated by different agonists working through the same receptor. 10,11 It has been proposed that ligands biased against recruiting β -arrestin-2, or showing preference for activating specific G-protein-mediated signal transduction pathways, will demonstrate diminished side effects.…”

Biased Opioid Ligands

“…Interestingly, two analogs in the same series with a t-butyl amide group ( N -( tert -butyl)-1-phenethyl-4-( N -phenylpropionamido)piperidine-4-carboxamide, MP105 ) and cyclopropyl amide group ( N -cyclopropyl-1-phenethyl-4-( N -phenylpropionamido)piperidine-4-carboxamide, MP103 ) instead of cycloheptyl amide moiety showed higher efficacy in the β-arrestin 2 assay compared to MP102, again suggesting that small changes in structure of the analog lead to differential signaling ( Table 1 ). A lead compound in this series MP102 [ 25 , 52 ] exhibited moderately potent analgesia with significantly reduced respiratory depression, constipation, and physical dependence while showing analgesic tolerance and reward behavior. The role of DOR agonism in the actions of MP102 may play a key role in vivo and needs to be investigated with future analog design.…”

Design synthesis and structure–activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands

“…Over hundred million people in the United States suffer from chronic and neuropathic pain. 1 The morphine structure was discovered in 1803 by the German pharmacist Serturner, but only in the last 40 years researchers have made important progress in opioid drug discovery 2–13 based on the natural endogenous opioid ligands. Including the molecularly cloned three opioid receptors (μ, δ and κ) and have a better understanding of mechanism of action, and the recent crystallographic analysis of μ and other opioid receptors.…”