Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity

Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

“…This finding led to the evaluation of a collection of chalcones and related compounds, leading to the discovery of two new families of potent PAMs of the α7 nicotinic channels-polyhydroxychalcones [18] and polyhydroxydiphenyl propanones. This permitted the identification of a new chemotype of α7 nAChRs PAMs and compounds that exhibit promising analgesic and neuroprotective activities [19][20][21].…”

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

“…Interestingly, these effects were not observed in a7 nAChR knock-out mice and were blocked by the a7nAChR antagonist MLA (Papke et al, 2015). A systematic screening of a library of small natural molecules (Greenpharma Natural compound library, Prestwick Chemical, France) combined with structure-activity relationship analysis lead to the discovery of hydroxylated chalcones as new PAMs targeting a7nAChRs (Balsera et al, 2014;Criado et al, 2016;Balsera et al, 2018). The compound 111 was characterized as a selective a7nAChR PAM (EC 50 ≈3 mM) by using two-electrode voltage-clamp (TEVC) recordings in Xenopus oocytes.…”

“…In CFA-injected rats, the compound 31 displayed analgesic effects similar to those obtained with PNU-120596 (Criado et al, 2016). However, these chalcone-derivate compounds have low aqueous solubility and short time of action in vivo (Balsera et al, 2018). To solve this issue, Balsera and collaborators reported the characterization of peptide-based carrier prodrugs of these compounds (Balsera et al, 2018).…”

“…However, these chalcone-derivate compounds have low aqueous solubility and short time of action in vivo (Balsera et al, 2018). To solve this issue, Balsera and collaborators reported the characterization of peptide-based carrier prodrugs of these compounds (Balsera et al, 2018). Despite the electrophysiological evidences showing inhibitory actions on the ACh-evoked currents, two peptide derivatives (i.e., comp19 and comp21) carrying the compound 31 showed a recovery of the mechanical hyperalgesia with a prolonged effect (Balsera et al, 2018).…”

“…To solve this issue, Balsera and collaborators reported the characterization of peptide-based carrier prodrugs of these compounds (Balsera et al, 2018). Despite the electrophysiological evidences showing inhibitory actions on the ACh-evoked currents, two peptide derivatives (i.e., comp19 and comp21) carrying the compound 31 showed a recovery of the mechanical hyperalgesia with a prolonged effect (Balsera et al, 2018). Conversely, other authors have studied the actions of peptides directly targeting a7nAChRs.…”