Differing Activity Profiles of the Stereoisomers of 2,3,5,6TMP-TQS, a Putative Silent Allosteric Modulator of α7 nAChR

Abstract

Many synthetic compounds to which we attribute specific activities are produced as racemic mixtures of stereoisomers, and it may be that all of the desired activity comes from a single enantiomer. We have previously shown this to be the case with the a7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) TQS, and the a7 ago-PAM 4BP-TQS. 2,3,5,6TMP-TQS, previously published as a "silent allosteric modulator" and an antagonist of a7 allosteric activation, shares the same scaffold with three chiral centers as the aforementioned compounds. We isolated the enantiomers of 2,3,5,6TMP-TQS and determined that the (-) isomer was a significantly better antagonist than the (+) isomer of the allosteric activation of both wild-type a7 and the non-orthosterically activatible C190A a7 mutant by the ago-PAM GAT107 (the active isomer of 4BP-TQS). In contrast (+)2,3,5,6TMP-TQS proved to be an a7 PAM. (-)2,3,5,6TMP-TQS was shown to antagonize the allosteric activation of a7 by the structurally unrelated ago-PAM B-973B as well as the allosteric activation of the TQS-sensitive a4b2L15'M mutant. In silico docking of 2,3,5,6TMP-TQS in the putative allosteric activation binding site suggested a specific interaction of the (-) enantiomer with a7T106, and allosteric activation of a7T106 mutants was not inhibited by (-)2,3,5,6TMP-TQS, confirming the importance of this interaction and supporting the model of the allosteric binding site. Comparisons and contrasts between 2,3,5,6TMP-TQS isomers and active and inactive enantiomers of other TQS-related compounds identify the orientation of the cyclopentenyl ring to the plane of the core quinoline to be a crucial determinate of PAM activity.

The Allosteric Activation of α7 nAChR by α-Conotoxin MrIC Is Modified by Mutations at the Vestibular Site

“…We first docked MrIA, MrIB, and MrIC into the ECD AA site of α7 nAChR and tested whether the three molecules could bind to this site. The ECD AA site ligands investigated so far in the literature interact with this site by burying their hydrophobic parts deep into the cavity defined by the vestibular loop residues 87–93 and 98–106 [ 21 , 24 , 25 , 26 ]. The bottom of the cavity is formed by the α7 nAChR residues F33, L56, Q57, M58, I90, and L91.…”

The allosteric activation of α7 nAChR by α-conotoxin MrIC is modified by mutations at the vestibular site

“…We first docked MrIA, MrIB, and MrIC into the ECD AA site of α7 nAChR and tested whether the three molecules could bind to this site. The ECD AA site ligands investigated so far in the literature interact with this site by burying their hydrophobic parts deep into the cavity defined by the vestibular loop residues 87-93 and 98-106 (21,(25)(26)(27). The bottom of the cavity is formed by the α7 nAChR residues F33, L56, Q57, M58, I90, and L91.…”

“…The results showed effectively no change in ACh responses at this MrIC concentration (Supporting Figure 3A). Second, we co-applied 60 μM PNU-120596 + 50 μM MrIC in the absence and presence of 100 μM (-)2,3,5,6TMP-TQS ((-)TMP-TQS, Supporting Figure 1), a selective antagonist of the ECD AA site that has little effect on the orthosteric and TMD PAM site activity of α7 nAChR (27,30).…”

“…The α7T106 residue forms hydrophobic interactions with V11 MrIC and L16 MrIC and blocks the complete entry of the peptide into the AA site formed between the α7 nAChR subunits A and B. This mutation is also of interest since it responds to standalone applications of PNU-120596 in a (-)TMP-TQS-sensitive manner, suggestive of a role in receptor desensitization (27). Therefore, MrIC was docked into the three mutant receptors to investigate the different interactions associated with these mutations.…”

Bibliometric analysis of nicotinic acetylcholine receptors channel research (2000-2020)

“…Papke, Roger L. was the second highly published author (82 articles). His research focused on the mechanisms of nAChR ligands and signaling and contributed to addiction, pain, inflammation, and other medically important issues [ 21–23 ].…”