pgp - publications

Predict more pgp - ligand interactions now!

1. Mol Pharm. 2012 Mar 19. [Epub ahead of print]

Exploiting transport activity of P-glycoprotein at the blood-brain-barrier for
the development of peripheral cannabinoid type 1 receptor antagonists.

Wittgen HG, Greupink R, van den Heuvel JM, van den Broek PH, Dinter-Heidorn H,
Koenderink JB, Russel FG.

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 <b>23</b> exhibited a reduced accumulation (-38
± 2%) in these cells, which could be completely reversed by the P-gp/BCRP
inhibitor elacridar. In addition, <b>23</b> appeared to be a BCRP substrate,
whereas rimonabant was not. In rats, the in vivo brain/plasma concentration ratio
of <b>23</b> was significantly lower than for rimonabant (0.4 ± 0.1 vs. 6.2 ±
1.6, p < 0.001). Co-administration of elacridar resulted in an 11-fold increase
of the brain/plasma ratio for <b>23</b> (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 <b>23</b> 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.

PMID: 22428727 [PubMed - as supplied by publisher]