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Brain Pharmacokinetics of Non‐Imidazole Biphenyl H3 Receptor Antagonists: a Liquid Chromatography/Electrospray‐Mass Spectrometry and ex vivo Binding Study in Rats
Author(s) -
Vacondio Federica,
Silva Claudia,
Flammini Lisa,
Ballabeni Vigilio,
Barocelli Elisabetta,
Mor Marco
Publication year - 2012
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201100242
Subject(s) - chemistry , pharmacokinetics , in vivo , ex vivo , piperidine , stereochemistry , agonist , metabolite , mass spectrometry , high performance liquid chromatography , lipophilicity , electrospray , electrospray ionization , chromatography , receptor , pharmacology , in vitro , biochemistry , microbiology and biotechnology , biology , medicine
In the present article, we report on the kinetics of brain penetration in rats of the H3R antagonist 1,1′‐[1,1′‐biphenyl‐4,4′‐diylbis(methylene)]bis‐[piperidine] ( 1 ), which had shown a favorable in vitro pharmacological profile and in vivo potency in preventing scopolamine‐induced amnesia. Two different approaches were employed: high‐performance liquid chromatography/electrospray‐mass spectrometry (HPLC/ESI‐MS) and ex vivo binding against the labeled agonist [ 3 H]‐( R )‐ α ‐methylhistamine ([ 3 H]RAMHA). Starting from the structure of 1 , the rigid piperidine ring was replaced by a flexible dipropylamino group (see 2 ) or by a morpholino ring (see 3 ), endowed with lower basicity. The effect of replacement on rat plasma and brain disposition in the 24 h after administration was analyzed. High (μ M ) and persistent concentrations of 1 were found in rat plasma, while plasma levels were significantly lower (range: 0–200 n M ) for the other two derivatives. This could be explained, among other factors, by the higher stability, observed for 1 , to liver metabolic cleavage. The applied chemical modulation had an important effect on in vivo brain disposition, as, despite the comparable physico‐chemical properties, 2 did not show the tendency to accumulate within the brain, as stated by its brain vs. plasma concentration ratios, if compared to 1 . These structureproperty relationships should be taken into account in the pharmacokinetic optimization of new series of H3 receptor antagonists.