Synthesis and biological evaluation of new non-imidazole H3-receptor antagonists of the 2-aminobenzimidazole series.
A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group. We investigated whether the removal of the imidazole ring could allow retaining high affinity for the H(3)-receptor, thanks to the interactions undertaken by the 2-aminobenzimidazole moiety at the binding site. The imidazole ring of the lead was replaced by a basic piperidine or by a lipophilic p-chlorophenoxy substituent, modulating the spacer length from three to eight methylene groups; moreover, the substituents were moved to the 5(6) position of the benzimidazole nucleus. Within both the 2-alkylaminobenzimidazole series and the 5(6)-alkoxy-2-aminobenzimidazole one, the greatest H(3)-receptor affinity was obtained for the piperidine-substituted compounds, while the presence of the p-chlorophenoxy group resulted in a drop in affinity. The optimal chain length was different in the two series. Even if the new compounds did not reach the high receptor affinity shown by the imidazole-containing lead compound, it was possible to get good H(3)-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance.
Rivara
Mirko
M
Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, Italy.
Zuliani
Valentina
V
Cocconcelli
Giuseppe
G
Morini
Giovanni
G
Comini
Mara
M
Rivara
Silvia
S
Mor
Marco
M
Bordi
Fabrizio
F
Barocelli
Elisabetta
E
Ballabeni
Vigilio
V
Bertoni
Simona
S
Plazzi
Pier Vincenzo
PV
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D002733:Chlorophenols / Q000737:chemistry; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D002733:Chlorophenols; D006633:Histamine Antagonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; C029107:4-chlorophenol; C032727:piperidine; C029899:imidazole; C027391:2-aminobenzimidazole