Nicotinoyl-Tryptamine Derivatives as Potential Dual-Action Prodrugs for NAD⁺ Enhancement and Neuroprotection

A series of twelve hybrid molecules conjugates nicotinic acid (vitamin B3) to substituted tryptamine scaffolds through an amide bond, with eleven being new chemical entities. The series includes 4-hydroxy-, 5-methoxy-, 4-acetoxy-, 4-phosphoryloxy-, and N-alkyl-substituted variants, among them a direct nicotinoyl conjugate of psilocin (4-HO-DMT). These molecules are proposed as potential dual-action prodrugs: enzymatic hydrolysis of the amide bond in vivo would release free nicotinic acid, a NAD⁺ precursor active in the Preiss-Handler pathway, alongside pharmacologically active hydroxytryptamine derivatives capable of serotonergic receptor modulation. No synthesis or biological testing has been performed; this preprint presents the structural framework to stimulate further investigation.

Study at a glance

Abstract

A novel class of hybrid molecules is described in which nicotinic acid (vitamin B3) is covalently conjugated to substituted tryptamine scaffolds via an amide bond. Twelve compounds are presented in total; eleven represent new chemical entities. The series encompasses 4-hydroxy-, 5-methoxy-, 4-acetoxy-, 4-phosphoryloxy-, and N-alkyl-substituted variants, including a direct nicotinoyl conjugate of psilocin (4-HO-DMT). These molecules are proposed as potential dual-action prodrugs: enzymatic hydrolysis of the amide bond in vivo would liberate free nicotinic acid — a NAD⁺ precursor active in the Preiss-Handler pathway — alongside pharmacologically active hydroxytryptamine derivatives capable of serotonergic receptor modulation. No synthesis or biological testing has been performed; this preprint presents the structural framework to stimulate further investigation.