Muscarinic M1 receptor (antagonist)

Class

Topical 4% gel/lotion formulation of pirenzepine free base monohydrate — a long-marketed oral antimuscarinic (used since the 1980s for gastric ulcer in Europe/Asia, never previously approved in the US) — repurposed and reformulated by WinSanTor as a once-daily topical treatment for peripheral neuropathy.

Pathway

Blocks tonic M1-receptor-mediated cholinergic suppression of neuronal mitochondrial respiratory capacity; M1 blockade activates AMPK and relieves this suppression, which in diabetic mouse models and a Phase 2a human trial (24 weeks, topical) produced statistically significant regrowth of nerve fibers, measured as increased intraepidermal nerve fibre density (IENFD) at the ankle.

The muscarinic M1 receptor is one of five subtypes of receptor for acetylcholine, the neurotransmitter of the parasympathetic nervous system, and is expressed not only in the central nervous system and gastric mucosa but also on peripheral sensory neurons. Under normal conditions, tonic activation of M1 receptors on these neurons suppresses their mitochondrial respiratory capacity, limiting the energy available for axonal maintenance and repair. Blocking M1 with an antagonist relieves this suppression and activates AMPK, a cellular energy-sensing enzyme that promotes mitochondrial biogenesis and metabolic efficiency. This mechanism is of interest in peripheral neuropathy, a condition marked by progressive loss of small sensory nerve fibers in the skin and extremities, commonly arising from diabetes or other metabolic and toxic insults, for which no therapies directly promote nerve fiber regrowth. Applying an M1 antagonist topically, rather than systemically, is intended to concentrate the drug at the affected peripheral nerves while minimizing exposure of central and visceral tissues, where M1 and related muscarinic subtypes govern cognition, salivation, and gastrointestinal motility. This repurposing of a decades-known antimuscarinic compound as a localized formulation illustrates how established pharmacology can be redirected toward a distinct disease mechanism.