Dibasic non-imidazole histamine H3 receptor antagonists with a rigid biphenyl scaffold.
A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1'-[biphenyl-4,4'-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H3 antagonist with high binding affinity (pKi=9.47) at human H3 histamine receptor.
Morini
Giovanni
G
Dipartimento Farmaceutico, Università degli Studi di Parma, V. le G.P. Usberti 27/A, I-43100 Parma, Italy. giovanni.morini@unipr.it
Comini
Mara
M
Rivara
Mirko
M
Rivara
Silvia
S
Lorenzi
Simone
S
Bordi
Fabrizio
F
Mor
Marco
M
Flammini
Lisa
L
Bertoni
Simona
S
Ballabeni
Vigilio
V
Barocelli
Elisabetta
E
Plazzi
Pier Vincenzo
PV
D000818:Animals; D002460:Cell Line; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D006633:Histamine Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3