Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Abstract

Aim: To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine. Methods: The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5′-O-(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations. Results: The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K i values in the nanomolar range. In [ 35 S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing. Conclusion:The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N 17 position and the high hydrophobicity of the C 7 -thiophene group in its chemical structure.

Elucidating fentanyls differentiation from morphines in chemical and biological samples with surface‐enhanced Raman spectroscopy

“…Here, we employed a training cluster of five fentanyls (fentanyl, 3‐methylfentanyl, sufentanil, remifentanil, and carfentanil) and six morphines (morphine, codeine, heroin, 6‐monoacetylmorphine, thienorphine, and 030418 ) to test the classification possibility. Direct classification between two classes was obviously achievable.…”

SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

“…Moreover, some orvinols, including etorphine, buprenorphine, thienorphine, the BU08028 and BU08070 series, the BU08073 series, BU10038 and the OREX-1019 series, as well as the phenyl substituted analogs of buprenorphine, exhibited low affinity and/or potency to the nociceptin/orphanin FQ opioid peptide (NOP) receptor, and functional regulation of NOP receptor was involved in analgesia, locomotor activity, abuse liability and reward, as well as other behavioral changes. ,− Whether the unique profile of SLL-627 was correlated to its potential action toward the NOP was not investigated in this work. Due to high variability and heterogeneity of data currently available, it is also difficult to predict the potential affinity of an orvinol analog toward the NOP receptor, but the affinity to the NOP receptor is always lower than that of the MOR, which is consistently observed for all of the above orvinols and structure-related analogs identified as either opioids with additional NOP affinity or bifunctional MOR/NOP modulators.…”

RMD86, a thiophene derivative, promotes antinociceptive and antipyretic activities in mice

“…Although a potent antinociceptive effect was observed for abdominal contortions induced by acetic acid, and in both phases of the formalin test, RMD86 only managed to reduce the nociceptive response time during the first 30 min of testing. In comparison, Wen et al, (2011) [ 54 ] analyzing another thiophene derivative, found that the compound increased latency time to 2 h in the hot plate test, being even more effective than morphine which presented antinociceptive effect for approximately 1 h. Then, using pharmacological analysis, it was found that the thiophene derivative presented signs of mechanisms involving opioid receptors.…”