Literature DB >> 33642954

Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands.

Kamal P Pandey1, Zubair Ahmed Khan1, Lalit K Golani1, Prithu Mondal1, Yeunus Mian1, Farjana Rashid1, V V N Phani Babu Tiruveedhula1, Daniel E Knutson1, Dishary Sharmin1, Taukir Ahmed1, Sepideh Rezvanian1, Nicolas M Zahn1, Leggy A Arnold1, Jeffrey M Witkin1, James M Cook1.   

Abstract

Antinociceptive ligand HZ-166 is a GABAA α2/α3 receptor subtype-selective potentiator. It has been shown to exhibit anxiolytic-like effects in rodent and rhesus monkeys, as well as reduced sedative/ataxic liabilities. In order to improve the metabolic stability of HZ-166, the ethyl ester moiety was bioisosterically replaced with 2,4-disubstituted oxazoles and oxazolines. The new analogs of HZ-166 were synthesized, characterized, and evalutated for their biological activity and docked in the human full-length heteromeric α1β3γ2L GABAA receptor subtype CyroEM structure (6HUO). Importantly no sedation nor ataxia was observed on the rotorod for LKG-I-70 (6) or KPP-III-51 (6c) at 100 and 120 mg/kg, respectively. These was also no loss of righting response for either ligand.

Entities:  

Keywords:  GABAA receptor; bioisosteres; docking; metabolism; subtype selectivity

Year:  2020        PMID： 33642954      PMCID： PMC7909486          DOI： 10.24820/ark.5550190.p011.398

Source DB:  PubMed          Journal:  ARKIVOC        ISSN： 1551-7004            Impact factor:   1.140


  20 in total

1.  Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.

Authors:  Neil Collinson; Frederick M Kuenzi; Wolfgang Jarolimek; Karen A Maubach; Rosa Cothliff; Cyrille Sur; Alison Smith; Franklin M Otu; Owain Howell; John R Atack; Ruth M McKernan; Guy R Seabrook; Gerry R Dawson; Paul J Whiting; Thomas W Rosahl
Journal:  J Neurosci       Date:  2002-07-01       Impact factor: 6.167

2.  Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure.

Authors:  Bradford D Fischer; Stephanie C Licata; Rahul V Edwankar; Zhi-Jian Wang; Shengming Huang; Xiaohui He; Jianming Yu; Hao Zhou; Edward M Johnson; James M Cook; Roman Furtmüller; Joachim Ramerstorfer; Werner Sieghart; Bryan L Roth; Samarpan Majumder; James K Rowlett
Journal:  Neuropharmacology       Date:  2010-08-18       Impact factor: 5.250

3.  The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Authors:  J M Witkin; R Cerne; P G Davis; K B Freeman; J M do Carmo; J K Rowlett; K R Methuku; A Okun; S D Gleason; X Li; M J Krambis; M Poe; G Li; J M Schkeryantz; R Jahan; L Yang; W Guo; L K Golani; W H Anderson; J T Catlow; T M Jones; F Porreca; J L Smith; K L Knopp; J M Cook
Journal:  Pharmacol Biochem Behav       Date:  2019-02-27       Impact factor: 3.533

4.  Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Authors:  R M McKernan; T W Rosahl; D S Reynolds; C Sur; K A Wafford; J R Atack; S Farrar; J Myers; G Cook; P Ferris; L Garrett; L Bristow; G Marshall; A Macaulay; N Brown; O Howell; K W Moore; R W Carling; L J Street; J L Castro; C I Ragan; G R Dawson; P J Whiting
Journal:  Nat Neurosci       Date:  2000-06       Impact factor: 24.884

5.  Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam.

Authors:  Megan J Moerke; Guanguan Li; Lalit K Golani; James Cook; S Stevens Negus
Journal:  Behav Pharmacol       Date:  2019-08       Impact factor: 2.293

6.  Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.

Authors:  Michael M Poe; Kashi Reddy Methuku; Guanguan Li; Ashwini R Verma; Kelly A Teske; Douglas C Stafford; Leggy A Arnold; Jeffrey W Cramer; Timothy M Jones; Rok Cerne; Michael J Krambis; Jeffrey M Witkin; Enrique Jambrina; Sabah Rehman; Margot Ernst; James M Cook; Jeffrey M Schkeryantz
Journal:  J Med Chem       Date:  2016-11-28       Impact factor: 7.446

7.  Improved Synthesis of Anxiolytic, Anticonvulsant and Antinociceptive α2/α3-GABA(A)ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, as well as Neuropathic Pain.

Authors:  Guanguan Li; Lalit K Golani; Rajwana Jahan; Farjana Rashid; James M Cook
Journal:  Synthesis (Stuttg)       Date:  2018-10       Impact factor: 3.157

8.  A practical approach to the synthesis of 2,4-disubstituted oxazoles from amino acids.

Authors:  Tina Morwick; Matt Hrapchak; Molly DeTuri; Scot Campbell
Journal:  Org Lett       Date:  2002-08-08       Impact factor: 6.005

9.  AutoDock VinaXB: implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina.

Authors:  Mathew R Koebel; Grant Schmadeke; Richard G Posner; Suman Sirimulla
Journal:  J Cheminform       Date:  2016-05-18       Impact factor: 5.514
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  2 in total

1.  Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.

Authors:  Nicolas M Zahn; M S Rashid Roni; Gene T Yocum; Michelle J Meyer; Daniel A Webb; Md Yeunus Mian; James M Cook; Douglas C Stafford; Charles W Emala; Leggy A Arnold
Journal:  ACS Pharmacol Transl Sci       Date:  2022-02-01

2.  Hydrochloride Salt of the GABAkine KRM-II-81.

Authors:  Md Yeunus Mian; Branka Divović; Dishary Sharmin; Kamal P Pandey; Lalit K Golani; V V N Phani Babu Tiruveedhula; Rok Cerne; Jodi L Smith; Xingjie Ping; Xiaoming Jin; Gregory H Imler; Jeffrey R Deschamps; Arnold Lippa; James M Cook; Miroslav M Savić; James Rowlett; Jeffrey M Witkin
Journal:  ACS Omega       Date:  2022-07-27
  2 in total

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