Inhibition of choline uptake byN-cyclohexylcholine, a high affinity ligand for the choline transporter at the blood–brain barrier

Abstract

The blood-brain barrier (BBB) choline transporter (CHT) may have utility as a drug delivery vector for drugs that act in the central nervous system. Previous studies suggested the importance of hydrophobic moieties on the cationic nitrogen of choline for improved affinity for this transporter. In a pilot study, we therefore designed five novel N-cycloalkyl derivatives of choline, one of which showed promising inhibition properties. This choline analogue had a cyclohexyl (UMBB-5) moiety substituting one of the methyl groups attached to the cationic nitrogen in choline. In situ experimental data were obtained from in situ rat brain perfusion studies. The binding affinity for the BBB-choline transporter found for UMBB-5 was K(i)=1.9 microM. Comparative molecular field analysis (CoMFA) suggested that the cyclohexyl moiety orientates towards a steric favourable area. Taken together, the results of these in situ and in silico studies provide further evidence or restrictions that occur with binding to this brain drug delivery vector.

In vivo, in vitro and in silico methods for small molecule transfer across the BBB

“…BBB Carrier‐Mediated Transport systems (CMTs) and/or brain delivery vectors, are a feasible option for small molecules to cross the BBB and achieving CNS‐active drug candidates by hitting two targets: a CMT and the corresponding therapeutic target— via prodrug, drug, etc. Nowadays in vivo studies indicate that several compounds may be transported by some CMTs at the BBB 23, 24, 198, 275–288…”

“…Over 98% of small molecules intended for therapeutic use in the CNS never reach the market because of their inherent inability to cross the BBB 21, 22. The BBB effectively restricts delivery of valuable pharmaceuticals to the brain thereby presenting major therapeutic limitations toward the treatment of CNS diseases 23, 24. It is reported that 12% of all drugs are active in the CNS, but only 1% of all drugs are active in the brain for diseases other than affective disorders 25.…”

Comparative disposition of dimethylaminoethanol and choline in rats and mice following oral or intravenous administration

“…Choline transport is characterized by sodiumdependent high-affinity, sodium-independent low-affinity, and sodium-independent bloodbrain barrier transport mechanisms (Crowe et al, 2002;Lockman and Allen, 2002). The choline transporters of the blood brain barrier are inhibited by close structural analogs of choline and quaternary amines (Ferguson and Collier, 1994;Geldenhuys et al, 2005;Cai et al, 2007). Changes in the activity of these transporters induced by close analogues of choline has direct impact on levels of brain acetylcholine (Sterling et al, 1986).…”

“…Rats or mice administered [ 14 C]DMAE via intracerebral injection were observed with rapid clearance of DMAE and increases in brain levels of phosphatidylethanolamine, phosphotidylethanolamine, or other acid-soluble and lipid cholines (Schlenk, 1990). In female mice administered 0.1 mg/kg [1,[2][3][4][5][6][7][8][9][10][11][12][13][14]…”