title: Alkylene tether-length dependent gamma-aminobutyric acid type A receptor competitive antagonism by tacrine dimers.
abstract: Bis(7)-tacrine was previously demonstrated as an antagonist of gamma-aminobutyric acid type A (GABA(A)) receptors. In this study, the effects of a series of alkylene-linked tacrine dimers on GABA(A) receptors were examined. In radioligand binding assay, the analogues differed in binding affinity for GABA(A) receptors, and potency monotonically increased as the tether was shortened from nine to two methylenes. Bis(2)-tacrine, the shortest tacrine dimer, could displace [(3)H]muscimol from rat brain membranes with an IC(50) of 0.48 microM, which was 11, 13 and 525 times more potent than the GABA(A) receptor antagonist (+)-bicuculline, bis(7)-tacrine and tacrine, respectively. In whole-cell patch-clamp recordings, these dimeric tacrine analogues competitively antagonized GABA-induced inward current with a rank order of potency of bis(2)-tacrine>bicuculline>bis(7)-tacrine>bis(9)-tacrine>tacrine, and the potency of bis(2)-tacrine was 11, 18 and 487 times higher than that of (+)-bicuculline, bis(7)-tacrine and tacrine, respectively. Bis(2)-tacrine shifted the GABA concentration-response curve to the right in a parallel manner, and the inhibition was voltage-independent between -80 and +20 mV. It can be concluded that the shorter the alkylene linkage in tacrine dimers the stronger the binding affinity and higher the antagonistic effect on the GABA(A) receptor will be.
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Li
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carlier
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: Kan
authors.forename: Kwokmin
authors.initials: K
authors.lastname: Hui
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Zhiwang
authors.initials: Z
authors.lastname: Li
authors.forename: Keming
authors.initials: K
authors.lastname: Xiong
authors.forename: Ella Chow
authors.initials: EC
authors.lastname: Clement
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
authors.forename: Xiangou
authors.initials: X
authors.lastname: Liu
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Pang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000478:Alkylation / Q000187:drug effects; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005727:Ganglia, Spinal / Q000166:cytology; D020128:Inhibitory Concentration 50; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D013619:Tacrine; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline