A Comprehensive Monograph on D-Serine: From Endogenous Neuromodulator to Therapeutic Candidate

Introduction

The landscape of neuropharmacology was significantly altered by the discovery of substantial quantities of the D-enantiomer of serine in the mammalian brain.[1] This finding challenged the long-held dogma that D-amino acids were "unnatural" molecules, largely restricted to the cell walls of bacteria and the venoms of lower organisms.[1] D-Serine emerged not as a metabolic curiosity, but as a key physiological player in the central nervous system (CNS). Subsequent research has firmly established its role as a potent and primary endogenous co-agonist at the N-methyl-D-aspartate (NMDA) receptor, a critical component of the brain's primary excitatory neurotransmitter system.[2]

The scientific rationale for investigating D-Serine as a therapeutic agent is deeply rooted in the "glutamate hypofunction hypothesis" of schizophrenia. This influential theory posits that a core pathophysiological element of the disorder is diminished signaling through NMDA receptors.[5] Given that D-Serine's binding is an absolute requirement for NMDA receptor activation, its supplementation represents a mechanistically targeted strategy to restore normal glutamatergic tone. This monograph provides a comprehensive and critical evaluation of D-Serine, tracing its journey from a fundamental component of neurobiology to a clinical candidate for schizophrenia and other CNS disorders. It will cover its foundational chemistry, intricate endogenous regulation, molecular pharmacology, clinical evidence, safety profile, and future therapeutic prospects, offering a holistic perspective on its potential and challenges.

Section 1: Molecular and Physicochemical Profile