Molecular pharmacology
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Molecular pharmacology · Jan 2004
Hydroxy metabolites of the Alzheimer's drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21): their molecular properties, interactions with brain nicotinic receptors, and brain penetration.
3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), an Alzheimer's drug candidate, selectively stimulates alpha7 nicotinic acetylcholine receptors. It rapidly enters the brain after oral administration and enhances cognitive behavior. Less than 1% of orally administered DMXBA is recovered in the urine. ⋯ The hydroxy metabolites were much more polar than DMXBA, derived from their experimentally estimated octanol/water partition coefficients, and they entered the brain much less readily than DMXBA. Their contributions to the behavioral effects of orally administered DMXBA, if any, would probably be very small during short-term administration. Benzylidene anabaseines pharmacologically similar to the hydroxy metabolites, but which enter the brain more readily, may provide greater stimulation of alpha7 receptors in the whole organism.
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Molecular pharmacology · Jan 2004
Defining the propofol binding site location on the GABAA receptor.
The GABAA receptor is a target of many general anesthetics. The low affinity of general anesthetics has complicated the search for the location of anesthetic binding sites. Attention has focused on two pairs of residues near the extracellular ends of the M2 and M3 membrane-spanning segments, alpha1Ser270/beta2Asn265 (15' M2) and alpha1Ala291/beta2Met286 (M3). ⋯ Propofol protected, in a concentration-dependent manner, the cysteine substituted for beta2Met286 from reaction with pCMBS-. Propofol did not protect the cysteine substituted for the aligned alpha1 subunit position or the 15' M2 segment Cys mutants in either subunit. We infer that propofol may bind near the extracellular end of the betasubunit M3 segment.