In vitro characterization of potency, affinity and selectivity of H3-antagonists: from thioperamide to thioperamide unrelated imidazole derivatives.
This paper summarizes the findings obtained for three different series of original compounds designed as potential H3-antagonists starting from thioperamide structure. The compounds were tested in functional and binding assays to estimate their potency, affinity and selectivity for histamine H3 receptors. Among them, many non-thiourea/isothiourea derivatives acted as selective H3 competitive antagonists and, particularly, 4(5)-[2-[4(5)-cyclohexylimidazol-2-ylthio]ethyl] imidazole (dIII) proved to be the most potent H3 blocker vs (R)-alpha-methylhistamine in electrically-stimulated ileum. This imidazole derivative, devoid of thiourea dependent toxic effects, with high affinity displaced biphasically [3H]-N alpha-methylhistamine bound to rat brain H3 sites. Thus, such compound could be proposed as the prototype molecule for the development of new non-thiourea/isothiourea H3-antagonists and as experimental tool to explore the intriguing question of H3 receptor heterogeneity.
Barocelli
E
E
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Parma, Facoltà di Farmacia, Italy.
Ballabeni
V
V
Caretta
A
A
Bertoni
S
S
Bordi
F
F
Rivara
S
S
Silva
C
C
Mor
M
M
Impicciatore
M
M
D000818:Animals; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008745:Methylation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D006633:Histamine Antagonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; C052075:thioperamide