Conformationally Restricted GABA Analogs: From Rigid Carbocycles to Cage Hydrocarbons

Abstract

GABA was discovered to play an important role as the major inhibitory neurotransmitter in the adult mammalian CNS 60 years ago. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. In an effort to increase the lipophilicity and to reduce conformational flexibility of GABA itself, a polycyclic or cage hydrocarbon framework can be introduced into the 3D structure of GABA in order to better control the binding. This article explores the available synthetic methods, properties and activity of carbocyclic (cyclopropanes, cyclobutanes and cyclohexanes) and cage (adamantane and others) hydrocarbons - analogs of GABA with conformationally rigid carbon skeletons.

Three-component reaction of small-ring cyclic amines with arynes and acetonitrile

“…In addition, hydrolysis of the nitrile products to the corresponding carboxylic acids can afford chiral b-substituted g-aminobutyric acids. This class of compounds has recently yielded a number of new psychoactive small-molecule therapeutics, including the blockbuster drug pregabalin (Lyricat), as well as vigabatrin, 32 gabapentin, 33 and atagabalin, currently in clinical development for treatment of insomnia. 34 In conclusion, we have developed a new three-component reaction between aziridines and azetidines, arynes and acetonitrile that leads to N-aryl-g-amino nitriles.…”

Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3‐Bis‐Pharmacophores, Exemplified by GABA

“…The various typical approaches have been reviewed by Levandovskiy et al. ; these involve introduction of bulky aliphatic units on the propylene linker of GABA or the incorporation of rings of different sizes, with either one common atom or bond with the GABA unit or bridging non‐contiguous atoms, into various mono‐, bi‐, or even polycyclic structures. Interestingly, many of these GABA analogues show remarkable and stereospecific cell‐biological activities at receptors and transport systems, as well as interesting pharmacological effects in vivo, in spite of often substantially increased molecular size and lipophilicity.…”

Welcome to ‘Gabaergic Drugs’

“…The prelimi nary communication from the Ramachandran group describes the synthesis of novel GABA derivatives for potential GABA pharmacological studies [9]. Shubina and coworkers provide an overview of the synthetic routes to, and properties of carbocyclic (cyclopropanes, cyclobutanes and cyclohexanes) and cage (adamantane and others) hydrocarbons -analogs of GABA with confor mationally rigid carbon skeletons [10]. Finally, although a relatively new topic, this issue also features an extensive review by Chebib of GABA C receptor pharmacology and its i mplications for myopia, learning and memory [11].…”