title: Exploiting transport activity of p-glycoprotein at the blood-brain barrier for the development of peripheral cannabinoid type 1 receptor antagonists.
abstract: Although the CB1 receptor antagonist/inverse agonist rimonabant has positive effects on weight loss and cardiometabolic risk factors, neuropsychiatric side effects have prompted researchers to develop peripherally acting derivatives. Here, we investigated for a series of 3,4-diarylpyrazoline CB1 receptor antagonists if transport by the brain efflux transporter P-gp could be used as a selection criterion in the development of such drugs. All 3,4-diarylpyrazolines and rimonabant inhibited P-gp transport activity in membrane vesicles isolated from HEK293 cells overexpressing the transporter, but only the 1,1-dioxo-thiomorpholino analogue 23 exhibited a reduced accumulation (-38 ± 2%) in these cells, which could be completely reversed by the P-gp/BCRP inhibitor elacridar. In addition, 23 appeared to be a BCRP substrate, whereas rimonabant was not. In rats, the in vivo brain/plasma concentration ratio of 23 was significantly lower than for rimonabant (0.4 ± 0.1 vs 6.2 ± 1.6, p < 0.001). Coadministration of elacridar resulted in an 11-fold increase of the brain/plasma ratio for 23 (p < 0.01) and only 1.4-fold for rimonabant (p < 0.05), confirming the involvement of P-gp and possibly BCRP in limiting the brain entrance of 23 in vivo. In conclusion, these data support the conception that efflux via transporters such as P-gp and BCRP can limit the brain penetration of CB1 receptor antagonists, and that this property could be used in the development of peripheral antagonists.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, The Netherlands.
authors.forename: Hanneke G M
authors.initials: HG
authors.lastname: Wittgen
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: Petra H H
authors.initials: PH
authors.lastname: van den Broek
authors.forename: Heike
authors.initials: H
authors.lastname: Dinter-Heidorn
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D063387:Cannabinoid Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077285:Rimonabant; D053719:Tandem Mass Spectrometry; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D063387:Cannabinoid Receptor Antagonists; D009363:Neoplasm Proteins; D010880:Piperidines; D011720:Pyrazoles; D044005:Tetrahydroisoquinolines; D011802:Quinidine; C083501:Elacridar; D000077285:Rimonabant