Synthesis and biological assays of new H3-antagonists with imidazole and imidazoline polar groups.
New histamine H3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives (2a-f) with tetramethylene chain (pKi 8.03-8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles (1a-i) and that of 2-alkylthioimidazolines (3a-h). In contrast, a general lowering of affinity (pKi 5.90-7.63) was observed for compounds of the last series (3a-h), with a complex dependence on the terminal lipophilic group and chain length.
Mor
M
M
Dipartimento Farmaceutico, Università degli Studi di Parma, Italy.
Bordi
F
F
Silva
C
C
Rivara
S
S
Zuliani
V
V
Vacondio
F
F
Morini
G
G
Barocelli
E
E
Ballabeni
V
V
Impicciatore
M
M
Plazzi
P V
PV
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3