Nelonicline (ABT-126): A Comprehensive Pharmacological and Clinical Development Review of a Selective α7 Nicotinic Acetylcholine Receptor Agonist

I. Executive Summary

Nelonicline, also known by its developmental code ABT-126, is an investigational small molecule drug originated by Abbott Laboratories (later AbbVie). It was designed as an orally active, selective agonist of the alpha-7 nicotinic acetylcholine receptor (α7 nAChR), a key modulator of neuronal signaling in the central nervous system. The development of nelonicline was founded on the well-established cholinergic hypothesis, which links cognitive deficits in neurodegenerative and psychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia, to dysfunction in the brain's acetylcholine systems. By selectively targeting the α7 nAChR, nelonicline was intended to enhance cholinergic transmission, thereby improving cognitive functions like memory, learning, and attention.

The compound demonstrated a promising preclinical and early clinical profile, characterized by high-affinity binding to its target, desirable pharmacokinetic properties including oral activity and brain permeability, and a metabolic pathway that minimized the potential for common drug-drug interactions. Across a broad Phase 2 clinical program, nelonicline consistently exhibited a favorable safety and tolerability profile, with adverse events generally being mild to moderate and comparable in frequency to placebo.