- Design and synthesis of N?(benzylpiperidinyl)?4?fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism
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Aims: Haloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog
- Déciga-Campos, Myrna,Espinosa-Juárez, Josué,González-Trujano, María Eva,López-Mu?oz, Francisco Javier,Melo-Hernández, Luis Alberto,Navarrete-Vázquez, Gabriel,Schepmann, Dirk,Torres-Gómez, Héctor,Wünsch, Bernhard
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- Structure-Activity Relationship, Pharmacological Characterization, and Molecular Modeling of Noncompetitive Inhibitors of the Betaine/γ-Aminobutyric Acid Transporter 1 (BGT1)
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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.
- 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.
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supporting information
p. 8834 - 8846
(2017/11/14)
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- 2-alkylidene hydroxycumaranone derivatives
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Compounds of the formula wherein R,R′, A,B,T and x have the meaning given in the specification possess uPA (urokinase-type plasminogen activator) antagonist activity and can be employed as antitumor and/or antimetastatic agents.
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