Abstract
A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([3H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H1 drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.
Highlights
IntroductionSince the early discovery of tight junctions linking brain endothelial cells to each other and impeding the blood-brain barrier (BBB) paracellular route, more recent biochemical insights have better illustrated the role played by xenobiotic transporters in the control of the drug access to the brain parenchyma as well as in many body interfaces such as the intestine
The blood-brain barrier (BBB), formed by the endothelial cells of brain capillaries, is known to efficiently restrict the brain access of many compounds, making it a challenge to develop new pharmacological agents targeting the central nervous system (CNS) [1].Since the early discovery of tight junctions linking brain endothelial cells to each other and impeding the BBB paracellular route, more recent biochemical insights have better illustrated the role played by xenobiotic transporters in the control of the drug access to the brain parenchyma as well as in many body interfaces such as the intestine
The ability of psychoactive drugs to permeate the BBB has been pictured as an absence of their transport by these ATP-binding cassette proteins (ABC) proteins and their ability to passively diffuse through the BBB
Summary
Since the early discovery of tight junctions linking brain endothelial cells to each other and impeding the BBB paracellular route, more recent biochemical insights have better illustrated the role played by xenobiotic transporters in the control of the drug access to the brain parenchyma as well as in many body interfaces such as the intestine. This knowledge has advanced our understanding of the dynamics and fate of drugs across membranes and cellular interfaces.
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