Role of Hydrophobic Substituents on the Terminal Nitrogen of Histamine in Receptor Binding and Agonist Activity: Development of an Orally Active Histamine Type 3 Receptor Agonist and Evaluation of Its Antistress Activity in Mice

Abstract

The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

“…It was identified as a potent H 3 R agonist with good selectivity over H 1 R (20‐fold) and H 4 R (93‐fold). Particularly, ( S )‐enantiomer 186 was favorable for binding with the hydrophobic region in TM6 and exhibited much higher affinity (13‐fold) than ( R )‐enantiomer . These observations indicated that human H 3 R receptor recognized the strictly enantiomeric structure of ligands.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…(Kitbunnadaj et al, 2005). Other lipophilic agonists have also been described in an extensive SAR study (Govoni et al, 2006), and an agonist (37) (human H 3 receptor K i = 0.17 nM, 77% efficacy) was active in vivo in mice in blocking aggression and stress (Ishikawa et al, 2010). Other H 3 receptor agonists have been described with novel structural variations, including immethridine (human H 3 receptor K i = 0.9 nM, 90% agonist efficacy), an analog of immepip wherein the highly basic piperidine moiety is replaced by a less basic pyridinyl moiety (Kitbunnadaj et al, 2004).…”

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity

“…Imidazole-containing agonists have shown some potential application in different therapeutic areas, such as mechanical nociception, 23 obesity, and diabetes mellitus (diet-induced obesity mice test) 24 and stress (rodent-intruder mice test). 21 Some data also support the hypothesis of cardioprotective effect of H 3 R receptor activation. 25,26 However, it is fair to say that imidazole-containing agonists may suffer from the same imidazole-related drawbacks that were associated with the first generation of imidazole-containing H 3 R antagonists (vide supra).…”

“…In sharp contrast, developing non-imidazole H 3 R agonists has not been very successful. The best agonists contain an imidazole ring − and, compared to the endogenous ligand histamine ( 1 ), these derivatives show similar [e.g., imbutamine ( 2 )] or significantly higher affinity (p K i ) and/or functional activity (pEC 50 ) on H 3 R [e.g., imetit ( 3 ), methimepip ( 4 ), and (1 S ,2 S )-2-(2-aminoethyl)-1-(1 H -imidazol-4-yl)­cyclopropane ( 5 )] (Figure A). Imidazole-containing agonists have shown some potential application in different therapeutic areas, such as mechanical nociception, obesity, and diabetes mellitus (diet-induced obesity mice test) and stress (rodent-intruder mice test) .…”

“…The best agonists contain an imidazole ring − and, compared to the endogenous ligand histamine ( 1 ), these derivatives show similar [e.g., imbutamine ( 2 )] or significantly higher affinity (p K i ) and/or functional activity (pEC 50 ) on H 3 R [e.g., imetit ( 3 ), methimepip ( 4 ), and (1 S ,2 S )-2-(2-aminoethyl)-1-(1 H -imidazol-4-yl)­cyclopropane ( 5 )] (Figure A). Imidazole-containing agonists have shown some potential application in different therapeutic areas, such as mechanical nociception, obesity, and diabetes mellitus (diet-induced obesity mice test) and stress (rodent-intruder mice test) . Some data also support the hypothesis of cardioprotective effect of H 3 R receptor activation. , However, it is fair to say that imidazole-containing agonists may suffer from the same imidazole-related drawbacks that were associated with the first generation of imidazole-containing H 3 R antagonists (vide supra).…”