Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities

The histamine H-3 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 H-3 autoreceptors reinforces histaminergic transmission, while antagonism of H-3 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.