1044-79-7Relevant academic research and scientific papers
Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)
J?rgensen, Lars,Al-Khawaja, Anas,Kickinger, Stefanie,Vogensen, Stine B.,Skovgaard-Petersen, Jonas,Rosenthal, Emil,Borkar, Nrupa,L?ffler, Rebekka,Madsen, Karsten K.,Br?uner-Osborne, Hans,Schousboe, Arne,Ecker, Gerhard F.,Wellendorph, Petrine,Clausen, Rasmus P.
supporting information, p. 8834 - 8846 (2017/11/14)
N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report the synthesis and structure-activity relationship of 71 analogues. We identify 26m as a more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity and an improved off-target profile compared to 5. We performed radioligand-based uptake studies at chimeric constructs between BGT1 and GAT3, experiments with site-directed mutated transporters, and computational docking in a BGT1 homology model based on the newly determined X-ray crystal structure of the human serotonin transporter (hSERT). On the basis of these experiments, we propose a binding mode involving residues within TM10 in an allosteric site in BGT1 that corresponds to the allosteric binding pocket revealed by the hSERT crystal structure. Our study provides first insights into a proposed allosteric binding pocket in BGT1, which accommodates the binding site for a series of novel noncompetitive inhibitors.
Pharmaceutical compositions and methods of treating hypertension
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, (2008/06/13)
Pharmaceutical compositions containing a group of heterocyclic compounds and their use in treatment of disorders and diseases of the cardiovascular system and/or in the treatment of superficial and deep allergic phenomena is described. These compounds used in the composition and/or methods are piperidine compounds linked by the nitrogen atom to a substituted or unsubstituted cycloalkyl, aryl or heterocyclic radical through the intermediary of a group selected from a lower-alkylene radical, a monoketo lower-alkylene radical or a hydroxy-lower-alkylene radical, or a bivalent radical of the formula --NH.CO.(CH2)n -- where n is 1, 2 or 3, STR1 or --0-(lower-alkylene)--. The piperidine ring is further substituted by an acylamino residue.
HETEROCYCLIC COMPOUNDS
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, (2008/06/13)
A group of heterocyclic compounds useful in the treatment of disorders and diseases of the cardiovascular system and/or in the treatment of superficial and deep allergic phenomena is described. These compounds are piperidine compounds linked by the nitrogen atom to a substituted or unsubstituted phenyl radical through the intermediary of a group selected from a lower-alkylene radical, a mono-keto lower alkylene radical or a hydroxy-lower-alkylene radical, or a bivalent radical of the formula EQU1 or--O--(lower-alkylene)-. The piperidine rings are further substituted by a benzamido, substituted benzamido or cyclohexylcarboxamido residue.
