Allosteric modulators of GABA(B) receptors: mechanism of action and therapeutic perspective

Abstract

gamma-aminobutyric acid (GABA) plays important roles in the central nervous system, acting as a neurotransmitter on both ionotropic ligand-gated Cl(-)-channels, and metabotropic G-protein coupled receptors (GPCRs). These two types of receptors called GABA(A) (and C) and GABA(B) are the targets of major therapeutic drugs such as the anxiolytic benzodiazepines, and antispastic drug baclofen (lioresal(R)), respectively. Although the multiplicity of GABA(A) receptors offer a number of possibilities to discover new and more selective drugs, the molecular characterization of the GABA(B) receptor revealed a unique, though complex, heterodimeric GPCR. High throughput screening strategies carried out in pharmaceutical industries, helped identifying new compounds positively modulating the activity of the GABA(B) receptor. These molecules, almost devoid of apparent activity when applied alone, greatly enhance both the potency and efficacy of GABA(B) agonists. As such, in contrast to baclofen that constantly activates the receptor everywhere in the brain, these positive allosteric modulators induce a large increase in GABA(B)-mediated responses only WHERE and WHEN physiologically needed. Such compounds are then well adapted to help GABA to activate its GABA(B) receptors, like benzodiazepines favor GABA(A) receptor activation. In this review, the way of action of these molecules will be presented in light of our actual knowledge of the activation mechanism of the GABA(B) receptor. We will then show that, as expected, these molecules have more pronounced in vivo responses and less side effects than pure agonists, offering new potential therapeutic applications for this new class of GABA(B) ligands.

Keywords: Baclofen; allosteric modulators; anxiety; class C GPCRs.; drug addiction.

Fig. (1)

Expected structure of the heterodimeric GABA_B receptor in its inactive (left) and active (right) states. This receptor is made of two homologous subunits, GABA_B1 (in the front, in black) and GABA_B2 (in the back, in light grey). Each subunit is made of two main domains, the extracellular Venus Flytrap domain (VFT) and the heptahelical domain (HD). GABA and other orthosteric GABA_B ligands are known to bind in the GABA_B1 VFT. No known ligand bind at the equivalent site in GABA_B2. Only the GABA_B2 HD appears to be responsible for G-protein coupling. These images were made using the coordinates of the dimer of mGlu1 VFTs in the inactive empty state (left) and those of the active Glu occupied state (right) [43], in association with a dimer of HD generated based on the proposed model of the dimer of rhodopsin [47].

Fig. (2)

Structure of the two PAMs identified for the GABA_B receptor.

Fig. (3)

The PAMs increase both the potency and efficacy of GABA on the GABA_B receptor. Data were obtained from membranes prepared from HEK 293 cells expressing GABA_B1, GABA_B2 and the Gαo proteins. GTPγS binding was measured in the presence of the indicated concentration of GABA with (open triangles) or without (closed squares) 100 µM CGP7930. This figure is adapted from [3].

Fig. (4)

Schematic view of the mechanism of action of GABA_B PAMs as based on the proposed activation mechanism of this heterodimeric receptor. By stabilizing the closed state of the GABA_B1 VFT (dark grey), Ca²⁺ increases GABA affinity and potency. By stabilizing the active conformation of the GABA_B2 HD, small molecule PAMs increase both the potency and efficacy of agonists. The absence of agonist activity of these molecule may be due to their difficulty in promoting the relative movement between the subunits, a change that is proposed to play a critical role in receptor activation.

Fig. (5)

Major difference in the effect of agonists and PAMs acting at the GABA_B receptor. Scheme illustrate biological responses resulting from the physiological activity of the GABA_B receptor. In plain thick line is the response mediated under control condition. In the presence of a pure agonist, the receptor is always activated, with a decline resulting from the desensitization of the system and tolerance to the drug (dashed thick line). In contrast the PAM does not activate the system unless GABA is released close to the receptor. As such, the PAM enhances the response mediated by physiologically released GABA, enhancing the GABA mediated response, WHEN and WHERE needed (dashed thin line).