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The classic muscarinic acetylcholine receptor (mAChR) agonist carbamoylcholine (carbachol) does not seem to be the most obvious lead for the development of selective ligands at nicotinic acetylcholine receptors (nAChRs). In the past, however, N-methylations of carbachol have provided N-methylcarbamoylcholine and N,N-dimethylcarbamoylcholine (DMCC), which(More)
A series of acyclic and heterocyclic analogues of carbacholine (1) was synthesized using N-methylcarbacholine (MCC, 2), N,N-dimethylcarbacholine (DMCC, 3), and the corresponding tertiary amine (4) as leads. Whereas nicotinic acetylcholine receptor affinity was determined using [3H]nicotine as the radioactive ligand, [3H]oxotremorine-M ([3H]Oxo-M) and(More)
In a recent study, EF1502 [N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo [d]isoxazol-3-ol], which is an N-substituted analog of the GAT1-selective GABA uptake inhibitor exo-THPO (4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), was found to inhibit GABA transport mediated by both GAT1 and GAT2 in human(More)
A series of lipophilic diaromatic derivatives of the glia-selective GABA uptake inhibitor (R)-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol [(R)-exo-THPO, 4] were synthesized via reductive amination of 3-ethoxy-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-one (9) or via N-alkylation of O-alkylatedracemic 4. The effects of the target compounds on GABA uptake(More)
3-Isoxazolols substituted in the 5-position by pyrrolidinyl or piperidyl (referred to, respectively, as PYOLs and PIOLs; see Figure 2 for structures) were designed and synthesized as analogues of the potent and specific GABAA agonist THIP. Activity in the series was markedly dependent upon positional isomerism in the structures. Isomers in which the(More)
We have previously defined the concept of functional partial agonism as the partial agonist responses recorded in brain slices after administration of full ionotropic glutamate receptor agonists and competitive antagonists at fixed ratios. Functional partial agonism can be established at any level of maximal response, depending on the molar ratio of agonist(More)
The inhibitory action of bicyclic isoxazole gamma-aminobutyric acid (GABA) analogues and their 4,4-diphenyl-3-butenyl (DPB) substituted derivatives has been investigated in cortical neurones and astrocytes as well as in human embryonic kidney (HEK 293) cells transiently expressing either mouse GABA transporter-1 (GAT-1), GAT-2, -3 or -4. It was found that(More)
The N-4,4-diphenyl-3-butenyl derivative of the glial selective gamma-aminobutyric acid (GABA) uptake inhibitor 4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridin-3-ol (N-DPB-THPO), was tested for its ability to block sound-induced seizures in the audiogenic seizure-susceptible Frings mouse model of epilepsy. Following intracerebroventricular (i.c.v.)(More)
5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAA agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12),(More)