Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABA receptor and Ca2.2 channel.

In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1β2γ2L γ-aminobutyric acid type A receptor (GABAR), and the human voltage-gated N-type calcium channel (Ca2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity: α9α10 > α7 > α3β2 ≅ α3β4, indicating that β2/β4 subunits are relatively less important for their activity.

Potentiation of the GABAR reveals variable energetic contributions by etiocholanolone and propofol.

The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor.

Chemical, Pharmacological, and Structural Characterization of Novel Acrylamide-Derived Modulators of the GABA Receptor.

Acrylamide-derived compounds have been previously shown to act as modulators of members of the Cys-loop transmitter-gated ion channel family, including the mammalian GABA receptor. Here we have synthesized and functionally characterized the GABAergic effects of a series of novel compounds (termed "DM compounds") derived from the previously characterized GABA and the nicotinic 7 receptor modulator (E)-3-furan-2-yl--p-tolyl-acrylamide (PAM-2). Fluorescence imaging studies indicated that the DM compounds increase apparent affinity to the transmitter by up to 80-fold in the ternary GABA receptor.

Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor.

The positive allosteric modulators (PAMs) of the α7 nicotinic receptor -(5-Cl-2-hydroxyphenyl)-'-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and ()-3-(furan-2-yl)--(-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α-, α+/β-, and γ+/β-), as well as the orphan α+/γ- interface, modify receptor potentiation by NS-1738 and PAM-2.