Synthesis and pharmacological evaluation of novel selective MOR agonist 6β-pyridinyl amidomorphines exhibiting long-lasting antinociception

Abstract

It was previously reported that 6β-aminomorphinan derivatives show high affinity for opiate receptors. Novel 6β-heteroarylamidomorphinanes were designed based on the MOR selective antagonist NAP. The 6β-aminomorphinanes were prepared with stereoselective Mitsunobu reaction and subsequently acylated with nicotinic acid and isonicotinic acid chloride hydrochlorides. The receptor binding and efficacy were determined in vitro and the analgesic activity was studied in vivo. The in vitro studies revealed moderate selectivity for MOR. At least two compounds in this series exhibited long-acting analgesic response when administered subcutaneously and intracerebroventricularly. When the substances were given intracerebroventricularly to mice, they showed analgesic potency comparable to morphine.

Fluorescently Labeled Morphine Derivatives for Bioimaging Studies

“…As we also wished to maintain the native stereochemistry of the C-6 position a double Mitsunobu approach was employed to install this amine, noting that the Mitsunobu reaction has previously been reported to invert this stereocenter in closely related opiates. [22][23][24][25] Accordingly, 6-OH was first inverted using benzoic acid under Mitsunobu conditions followed by saponification of the resultant ester to give the 6-isomorphine derivative Two different approaches for ester and amide conjugation were trialed. The first, using an acid chloride, yielded compounds 1 and 3 following phenolic deprotection (Scheme 2).…”

“…An amine moiety was subsequently introduced into the 6-position to provide a point of attachment which retains the capacity to act as a hydrogen bond donor as per the 6-OH of morphine after the linker has been attached. As we also wished to maintain the native stereochemistry of the C-6 position, a double Mitsunobu approach was employed to install this amine, noting that the Mitsunobu reaction has previously been reported to invert this stereocenter in closely related opiates. − Accordingly, 6-OH was first inverted using benzoic acid under Mitsunobu conditions followed by saponification of the resultant ester to give the 6-isomorphine derivative 7 . A comparison of the NMR spectra of compounds 6 and 7 (Supporting Information, Figure S1) demonstrated stereospecific inversion of this chiral center.…”

Oxidative Metabolism as a Modulator of Kratom’s Biological Actions

“…Tail flick antinociception in 129Sv6 mice was determined using the radiant heat tail flick technique using an Ugo Basile model 37360 instrument as previously described. ,, 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.…”

“…EC described. 7,76,78 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.…”

Herbicidal activity and molecular docking study of novel PPO inhibitors

“…J1 and different types of phenols were used as the raw materials in the preparation of intermediate J2. Subsequently, J2 was reacted with thionyl chloride in DCM to obtain the active intermediate J3 (Jones et al 2018;Urai et al 2017). J3 could be reacted directly with compound J5 without purification to obtain the final product J6 (Cui et al 2017;Meng and Szostak 2016;Wang et al 2014).…”