Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2CReceptor Agonists

2001 ◽  
Vol 44 (6) ◽  
pp. 1003-1010 ◽  
Author(s):  
James J. Chambers ◽  
Deborah M. Kurrasch-Orbaugh ◽  
Matthew A. Parker ◽  
David E. Nichols
Keyword(s):  
Conformationally Restricted ◽  
Pharmacological Evaluation ◽  
Enantiospecific Synthesis

scholarly journals Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands

2011 ◽  
Vol 26 (3) ◽  
pp. 341-349 ◽  
Author(s):  
Ramakrishna V.S. Nirogia ◽  
Ramasastri Kambhampati ◽  
Anand V. Daulatabad ◽  
Parandhama Gudla ◽  
Mohammad Shaikh ◽  
...  
Keyword(s):  
Receptor Ligands ◽  
Design Synthesis ◽  
Conformationally Restricted ◽  
Pharmacological Evaluation

Synthesis and pharmacological evaluation of conformationally restricted phenothiazine analogues

1982 ◽  
Vol 25 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Cor J. Grol ◽  
Durk Dijkstra ◽  
Wim Schunselaar ◽  
Ben H. C. Westerink ◽  
Arnold R. Martin
Keyword(s):  
Conformationally Restricted ◽  
Pharmacological Evaluation

Synthesis and pharmacological evaluation of conformationally restricted κ-opioid receptor agonists

MedChemComm ◽  
2016 ◽  
Vol 7 (12) ◽  
pp. 2368-2380 ◽  
Author(s):  
Yvonne Wenker ◽  
Michael Soeberdt ◽  
Constantin Daniliuc ◽  
Sonja Ständer ◽  
Dirk Schepmann ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Fine Tuning ◽  
Receptor Agonists ◽  
Conformationally Restricted ◽  
Pharmacological Evaluation ◽  
Pharmacokinetic Properties ◽  
Opioid Receptor Agonists

Additional N- and O-atoms in the bicyclic scaffold increase polarity and allow fine tuning of pharmacodynamic and pharmacokinetic properties of novel κ agonists.

ChemInform Abstract: SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF CONFORMATIONALLY RESTRICTED PHENOTHIAZINE ANALOGUES

1982 ◽  
Vol 13 (27) ◽  
Author(s):  
C. J. GROL ◽  
D. DIJKSTRA ◽  
W. SCHUNSELAAR ◽  
B. H. C. WESTERINK ◽  
A. R. MARTIN
Keyword(s):  
Conformationally Restricted ◽  
Pharmacological Evaluation

scholarly journals Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

2021 ◽  
Vol 9 ◽  
Author(s):  
Stefanie Kickinger ◽  
Maria E. K. Lie ◽  
Akihiro Suemasa ◽  
Anas Al-Khawaja ◽  
Koichi Fujiwara ◽  
...  
Keyword(s):  
Binding Mode ◽  
Gaba Transporter ◽  
Pharmacological Characterization ◽  
Design Synthesis ◽  
Conformationally Restricted ◽  
Pharmacological Evaluation ◽  
Mammalian Cell Lines ◽  
Molecular Determinants ◽  
Competitive Inhibitors ◽  
Gaba Transporter 1

The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1S,2S,5R)-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [3H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N-methylated analog (2) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (pKB value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α1β2γ2 GABAA receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N-methylated 2 was completely devoid of activity at GABAA receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico-guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.

Synthesis and pharmacological evaluation of enantiomerically pure endo-configured KOR agonists with 2 azabicyclo[3.2.1]octane scaffold

2021 ◽  
Author(s):  
Bernhard Wuensch ◽  
Hendrik Jonas ◽  
Daniele Aiello ◽  
Bastian Frehland ◽  
Kirstin Lehmkuhl ◽  
...  
Keyword(s):  
Bioactive Conformation ◽  
Enantiomerically Pure ◽  
Conformationally Restricted ◽  
Pharmacological Evaluation

Conformationally restricted bicyclic KOR agonists 10 with an endo configured amino moiety were synthesized to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2-5. A seven-step, chiral...

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