LASSBio‐881: an N‐acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation

Abstract

Background and purpose:Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881. Experimental approach: Modulation of capsaicin (CAP)-and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception. Key results: LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC50 of 14 mM, and inhibited proton-gated currents by 70% at 20 mM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP-or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7-11 days after nerve ligation, at a dose of 300 mmol·kg -1 ·day -1 p.o. At this dose, hyperthermia was not observed within 4 h following oral administration. Conclusions and implications:LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio-881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

“…On the other hand, compound 2d did not show a 3 J CH coupling in the same experiments, possibly due to the minor sp 2 amide nitrogen character and the longer length of the C-N bond, which results in a decrease in the rotational barrier compared to the other compounds (1, 2a-c). Because of this small barrier, 2d does not possess the fixed trans conformation necessary for 3 J CH coupling in this series. In addition, 3 J CH coupling of the amide N-1 H and imine 13 C=N was present in all compounds, indicating the similar chemical environments with no great differences in conformation for this moiety of NAH compounds.…”

“…Because of this small barrier, 2d does not possess the fixed trans conformation necessary for 3 J CH coupling in this series. In addition, 3 J CH coupling of the amide N-1 H and imine 13 C=N was present in all compounds, indicating the similar chemical environments with no great differences in conformation for this moiety of NAH compounds. The Gibbs free energy of activation (∆G ≠ ) related to the transition state among one conformer and another can be calculated using Equation 1.…”

“…Reagents and conditions: (a) benzamidine hydrochloride, Na/EtOH, rt, 9 h, 50%; (b) POCl 3 , 100 °C, 1 h, 98%; (c) Zn, AcOH, THF, 60 °C, 23 h, 50%.…”

“…The bioactive N-acylhydrazone (NAH) moiety has been identified in a great number of lead compounds that act on different types of molecular targets [1][2][3][4]. Because of the assemblage of amide and imine functions, NAH compounds may exist as C=N double bond stereoisomers (E/Z) (Scheme 1) and as syn/antiperiplanar conformers about the amide CO-NH bond (Scheme 1) [5].…”

α‐Spinasterol: a COX inhibitor and a transient receptor potential vanilloid 1 antagonist presents an antinociceptive effect in clinically relevant models of pain in mice

“…Compounds with a multi‐target action, for instance, on both TRPV1 receptor and COX enzymes, might improve the efficacy and minimize the adverse effects caused by TRPV1 antagonism or COX inhibition (Tributino et al, ). Several COX inhibitors and TRPV1 antagonists have been shown attenuate postoperative pain (Whiteside et al, ; Uchytilova et al, ).…”