No abstract

1 Studies with knockout mice lacking mdr1a P-glycoprotein (P-gp) have previously shown that blood-brain barrier P-gp is important in preventing the accumulation of several drugs in the brain. 2 Asimadoline (EMD 61753) is a peripherally selective k-opioid receptor agonist which is under development as a therapeutic analgaesic. From the structural characteristics of this drug and its peripheral selectivity, we hypothesized that it is transported by P-gp. 3 Using a pig-kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P-gp and the human MDR1 P-gp. 4 Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brain. In line with this accumulation di erence, mdr1a/1b (7/7) mice are at least 8 fold more sensitive to the sedative e ect of asimadoline than wild-type mice. 5 Interestingly, the oral uptake of asimadoline was not substantially altered in mdr1a/1b (7/7) mice. 6 Our results demonstrate that for some drugs, P-gp in the blood-brain barrier can have a therapeutically bene®cial e ect by limiting brain penetration, whereas at the same time intestinal Pgp is not a signi®cant impediment to oral uptake of the drug.

Keywords: Natural products / Canthin-6-ones / Indole alkaloids / Chiral sulfoxides / Quantum chemical calculations A unique set of thiomethylated canthin-6-one derivatives was isolated from Boletus curtisii. The bright yellow color of this mushroom is caused by two optically active canthin-6-one sulfoxides for which the names curtisin and 9-deoxycurtisin are proposed. The structures of the new compounds were established by MS and NMR methods and the absolute con-

No abstract