Dibasic biphenyl H3 receptor antagonists: Steric tolerance for a lipophilic side chain.
Within a series of histamine H(3)-antagonists characterized by a biphenyl core and two basic groups, we identified (S)-1-{[4'-((2-methylpyrrolidin-1-yl)methyl)biphenyl-4-yl]methyl}piperidine as a lead scaffold to introduce an additional lipophilic chain at the benzylic carbon close to the pyrrolidine ring. A series of derivatives was synthesized and tested for their binding affinity at human and rat histamine H(3) receptors, and for their antagonist potency. For compounds with two chiral centers, the synthetic procedure provided mixtures of diastereomeric couples, which were separated by flash chromatography. Combination of experimental NMR data and molecular dynamics simulation allowed the assignment of absolute stereochemistry, based on characteristic differences detected within each diastereomeric couple. The additional lipophilic group was tolerated by the receptor, supporting the hypothesis that the two regions described within the H(3) receptor binding site can be simultaneously occupied by antagonists. Diastereoisomers with opposite chirality at the benzylic carbon showed limited or no stereoselectivity at both human and rat receptors.
Dipartimento Farmaceutico, Università degli Studi di Parma, V.le G.P. Usberti 27/A, I-43124 Parma, Italy.
Fabrizio
F
Bordi
Silvia
S
Rivara
Elisa
E
Dallaturca
Caterina
C
Carmi
Daniele
D
Pala
Alessio
A
Lodola
Federica
F
Vacondio
Lisa
L
Flammini
Simona
S
Bertoni
Vigilio
V
Ballabeni
Elisabetta
E
Barocelli
Marco
M
Mor
D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D006633:Histamine Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3