Scaffold variations in amine warhead of histamine H3 receptor antagonists

• Some amine warhead variations generate several different leads for histamine H3 receptor antagonists/inverse agonists.
• Robust pharmacophore for this GPCR subtype with numerous possibilities for variations.
• Pharmacokinetic and toxicological aspects can be structurally adopted in newly designed ligands.

The histamine H3 receptor (H3R) is involved in numerous regulatory neurotransmission processes and therefore, is a prominent target for centrally occurring disease with some promising clinical candidates. Previous research resulted in the identification of a core pharmacophore blueprint for H3R antagonists/inverse agonists, which when inserted in a molecule, mostly ensures acceptable affinity. Nevertheless, variations of scaffold and peripheral areas can increase potency and pharmacokinetic profile of drug candidates. The variations in amine scaffolds of antagonists for this aminergic GPCR are of special importance.