Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4-Aminocrotonic and 4-Aminotetrolic Acids

Abstract

Analogues of the neurotransmitter GABA containing unsaturated bonds are restricted in the conformations they can attain. This review traces three such analogues from their synthesis to their use as neurochemicals. trans-4-Aminocrotonic acid was the first conformationally restricted analogue to be extensively studied. It acts like GABA across a range of macromolecules from receptors to transporters. It acts similarly to GABA on ionotropic receptors. cis-4-Aminocrotonic acid selectively activates bicuculline-insensitive GABAC receptors. 4-Aminotetrolic acid, containing a triple bond, activates bicuculline-sensitive GABAA receptors. These findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations. These and related analogues are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors.

Intramolecular Catalytic Hydrogen Atom Transfer (CHAT)

“…The involvement of a nitrogen atom is particularly important in formation of bioactive materials, such as unsaturated amino acids. The unsaturated (α,β)-dehydroamino acids, for instance, are important pharmaceutical targets. , As a model for CHAT -assisted amino–imino tautomerization, we employed the conversion of amino isomer of the unsaturated GABA (γ-aminobutyric acid), H 2 N–CH = CH–CH 2 –C­(O)­OH, into its imino (enamine) form, HN = CH–CH 2 –CH 2 –C­(O)­OH. Our calculations revealed that the Gibbs energy barrier for amino–imino tautomerization via a CHAT mechanism, indeed, is lower than the barrier for direct isomerization by more than a factor of 2 (30.55 vs 65.67 kcal/mol).…”

“…The unsaturated (α,β)-dehydroamino acids, for instance, are important pharmaceutical targets. 67,68 As a model for CHATassisted amino−imino tautomerization, we employed the conversion of amino isomer of the unsaturated GABA (γaminobutyric acid),…”

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

“…Muscimol is such a conformationally restricted GABA analogue, containing both a ring structure and double bonds, acting selectively on GABA A receptors (Johnston et al, 1968). One of us (Graham Johnston) has reviewed unsaturated analogues of GABA (Johnston, 2016) in a special issue of Neurochemical Research honouring the other (Philip Beart; may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists.…”

“…Muscimol is such a conformationally restricted GABA analogue, containing both a ring structure and double bonds, acting selectively on GABA A receptors (Johnston et al., 1968). One of us (Graham Johnston) has reviewed unsaturated analogues of GABA (Johnston, 2016) in a special issue of Neurochemical Research honouring the other (Philip Beart; Lawrence & Gundlach, 2016). This was reciprocating a special issue of Neurochemical Research honouring a significant birthday of the other (Graham Johnston; Beart & Balcar, 2009).…”

Design, Docking Simulations, Synthesis, and in vitro and in vivo Behavioral Assessment of m‐Aminobenzoic Acid Analogues as GABA‐AT Inhibitors

“…Additionally, molecules unable to cross the BBB, must rely on various endogenous transporters. [13] Some GABA analogues that are unsaturated between the amino and carboxylic group, including cis-amino crotonic acid, trans-amino crotonic acid, and aminotetrolic acid, are characterized by an increased specificity to recognize GABAergic receptors; [14][15][16][17] similarly, cyclic systems, such as gabaculine, a naturally occurring neurotoxin, analog of m-aminobenzoic acid (MABA) and GABA-AT inhibitor, are able to cross the BBB (Figure 1) [18][19][20] and these structures are closely related with our proposed compounds in the Table 1.…”