Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R 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 H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R 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 H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.