Procognitive Properties of Drugs with Single and Multitargeting Hsub3/sub Receptor Antagonist Activities

摘要

Summary The histamine H3 receptor (H3R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3R antagonists/inverse agonists involved studies of structure–activity relationships, cross‐affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma‐aminobutyric acid (GABA). The H3R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small‐molecule H3R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N‐methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3R antagonists/inverse agonists and dual H3R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.