Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.

Figure 1

Role of the cholinergic system in depression. The cholinergic hypothesis of depression postulates a hyperactivity of the cholinergic system over that of the adrenergic system in the brain. Choline (the rate-limiting precursor to endogeneous ACh) crosses the blood–brain barrier to enter the brain and is actively transported into the cholinergic presynaptic terminals by an active uptake mechanism. The neurotransmitter ACh is synthesized from choline and acetyl coenzyme A, catalyzed by the enzyme choline acetyl transferase. ACh is sequestered into secretory vesicles by vesicular ACh transporters. Once released from the presynaptic terminals, ACh can interact with a variety of presynaptic and postsynaptic receptors. Two classes of the cholinergic ACh receptors are muscarinic (G protein-coupled) and nicotinic (ionotropic). Once activated, nAChRs form transient open cationic channels that allow the ions Na⁺, K⁺, and Ca²⁺ to flow across the plasma membrane and induce cellular responses. Prolonged exposure to ACh or nicotinic agonist causes a gradual decrease in the rate of this ionic response, leading to a high affinity, longer-lasting functionally inactive state, referred to as desensitization. ACh has its signal terminated primarily by the enzyme AChE, unlike many other monoaminergic neurotransmitters where reuptake mechanisms predominate.

Scheme 1. Compound Structures

Figure 2

Selected nAChR subtypes. The high sensitivity (HS) α4β2-nAChR has a presumed α4/β2 subunit ratio of 2:3 and exhibits comparatively high sensitivity to nicotinic agonists, whereas the low sensitivity (LS) α4β2-nAChR, at which nicotinic agonists have lower observed potency, is composed presumably of α4 and β2 subunits in a 3:2 ratio.

Figure 3

Top view of X-ray crystal structures of Ac-, Ls-, and Ct-AChBPs. The figure was generated using PDB files 2BR7, 1I9B, and 4B5D by PyMOL.

Figure 4

Amino acid sequence alignment of the Ct-AChBP with extracellular domains of nAChR α4 or β2 subunits. Green boxes highlight positions of key residues of the α4 subunit, and blue boxes outline key residues of the β2 subunit. Residue numeration refers to that for the human α4 subunit. (This is for the mature α4 subunit, not including cleavage of the leaders sequence including the translational start methionine residue.).

Figure 5

Homology model of the human α4β2-nAChR ECD including the ligand binding interface: (A) ribbon structure representation colored by subunit (yellow, α4; azure, β2) for the human α4β2-nAChR ECD and (B) superimposition of the modeled structure (in blue) with the experimental template from Ct-AChBP (in red).

Figure 6

Selected nicotinic benzazapine analogues.

Figure 7

X-ray crystal structure of the Ct-AChBP in complex with compound 2 or 29.