Agonists of the γ-aminobutyric Acid Type B (GABA) Receptor Derived from β-hydroxy and β-amino Difluoromethyl Ketones

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2018 Apr 17

PMID 29657102

Citations 5

Authors

Munia F Sowaileh

Amy E Salyer

Kuldeep K Roy

Jinu P John

James R Woods

Robert J Doerksen

Gregory H Hockerman

David A Colby

Affiliations

Soon will be listed here.

Abstract

β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.

Citing Articles

Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes.

Islam B, Kreusel K, Sulochana S, Nguyen A, Sowaileh M, Khatri H Bioorg Med Chem Lett. 2024; 113:129964.

PMID: 39284455 PMC: 11490360. DOI: 10.1016/j.bmcl.2024.129964.

Synthesis of α,α-Difluoro-β-amino Ketones from -Boc-α-Amidosulfones and Pentafluoro--diols.

Islam B, Sulochana S, Colby D J Org Chem. 2024; 89(9):6506-6512.

PMID: 38606727 PMC: 11429856. DOI: 10.1021/acs.joc.3c02181.

GABA Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators.

Nieto A, Bailey T, Kaczanowska K, McDonald P Curr Top Behav Neurosci. 2021; 52:81-118.

PMID: 34036555 DOI: 10.1007/7854_2021_232.

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses.

Citarella A, Gentile D, Rescifina A, Piperno A, Mognetti B, Gribaudo G Int J Mol Sci. 2021; 22(3).

PMID: 33573283 PMC: 7866854. DOI: 10.3390/ijms22031398.

The GABA Receptor-Structure, Ligand Binding and Drug Development.

Evenseth L, Gabrielsen M, Sylte I Molecules. 2020; 25(13).

PMID: 32646032 PMC: 7411975. DOI: 10.3390/molecules25133093.

References

Pirard B, Carrupt P, Testa B, Tsai R, Berthelot P, Vaccher C . Structure-affinity relationships of baclofen and 3-heteroaromatic analogues. Bioorg Med Chem. 1995; 3(11):1537-45. DOI: 10.1016/0968-0896(95)00144-6. View

Ong J, Bexis S, Marino V, Parker D, KERR D, Froestl W . Comparative activities of the enantiomeric GABA(B) receptor agonists CGP 44532 and 44533 in central and peripheral tissues. Eur J Pharmacol. 2001; 412(1):27-37. DOI: 10.1016/s0014-2999(00)00945-6. View

Han C, Kim E, Colby D . Cleavage of carbon-carbon bonds through the mild release of trifluoroacetate: generation of α,α-difluoroenolates for aldol reactions. J Am Chem Soc. 2011; 133(15):5802-5. DOI: 10.1021/ja202213f. View

Alstermark C, Amin K, Dinn S, Elebring T, Fjellstrom O, Fitzpatrick K . Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors. J Med Chem. 2008; 51(14):4315-20. DOI: 10.1021/jm701425k. View

Hinton T, Chebib M, Johnston G . Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors. Bioorg Med Chem Lett. 2007; 18(1):402-4. DOI: 10.1016/j.bmcl.2007.10.019. View

Guery S, Floersheim P, Kaupmann K, Froestl W . Syntheses and optimization of new GS39783 analogues as positive allosteric modulators of GABA B receptors. Bioorg Med Chem Lett. 2007; 17(22):6206-11. PMC: 2278029. DOI: 10.1016/j.bmcl.2007.09.023. View

Chen L, Sun B, Zhang Y, Xu T, Xia Z, Liu J . Discovery of a Negative Allosteric Modulator of GABAB Receptors. ACS Med Chem Lett. 2014; 5(7):742-7. PMC: 4094264. DOI: 10.1021/ml500162z. View

Xu F, Peng G, Phan T, Dilip U, Chen J, Chernov-Rogan T . Discovery of a novel potent GABA(B) receptor agonist. Bioorg Med Chem Lett. 2011; 21(21):6582-5. DOI: 10.1016/j.bmcl.2011.08.006. View

Han C, Salyer A, Kim E, Jiang X, Jarrard R, Powers M . Evaluation of difluoromethyl ketones as agonists of the γ-aminobutyric acid type B (GABAB) receptor. J Med Chem. 2013; 56(6):2456-65. DOI: 10.1021/jm301805e. View

10.

Froestl W, Mickel S, von Sprecher G, Diel P, Hall R, Maier L . Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J Med Chem. 1995; 38(17):3313-31. DOI: 10.1021/jm00017a016. View

11.

Mizukami K, Sasaki M, Ishikawa M, Iwakiri M, Hidaka S, Shiraishi H . Immunohistochemical localization of gamma-aminobutyric acid(B) receptor in the hippocampus of subjects with schizophrenia. Neurosci Lett. 2000; 283(2):101-4. DOI: 10.1016/s0304-3940(00)00939-3. View

12.

Mugnaini C, Pedani V, Casu A, Lobina C, Casti A, Maccioni P . Synthesis and pharmacological characterization of 2-(acylamino)thiophene derivatives as metabolically stable, orally effective, positive allosteric modulators of the GABAB receptor. J Med Chem. 2013; 56(9):3620-35. DOI: 10.1021/jm400144w. View

13.

Brown K, Roy K, Hockerman G, Doerksen R, Colby D . Activation of the γ-Aminobutyric Acid Type B (GABA(B)) Receptor by Agonists and Positive Allosteric Modulators. J Med Chem. 2015; 58(16):6336-47. PMC: 7485174. DOI: 10.1021/jm5018913. View

14.

Nguyen A, Khatri H, Woods J, Baldwin C, Fronczek F, Colby D . Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines. J Org Chem. 2018; 83(6):3109-3118. PMC: 8274396. DOI: 10.1021/acs.joc.7b03014. View

15.

Balerio G, Rubio M . Baclofen analgesia: involvement of the GABAergic system. Pharmacol Res. 2002; 46(3):281-6. DOI: 10.1016/s1043-6618(02)00147-0. View

16.

Froestl W . Chemistry and pharmacology of GABAB receptor ligands. Adv Pharmacol. 2010; 58:19-62. DOI: 10.1016/S1054-3589(10)58002-5. View

17.

Hanson S, Morlock E, Satyshur K, Czajkowski C . Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different. J Med Chem. 2008; 51(22):7243-52. PMC: 2645942. DOI: 10.1021/jm800889m. View

18.

Fah C, Hardegger L, Baitsch L, Schweizer W, Meyer S, Bur D . New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic alpha,alpha-difluoroketone hydrates. Org Biomol Chem. 2009; 7(19):3947-57. DOI: 10.1039/b908489d. View

19.

Dambrova M, Zvejniece L, Liepinsh E, Cirule H, Zharkova O, Veinberg G . Comparative pharmacological activity of optical isomers of phenibut. Eur J Pharmacol. 2008; 583(1):128-34. DOI: 10.1016/j.ejphar.2008.01.015. View

20.

Besnard J, Ruda G, Setola V, Abecassis K, Rodriguiz R, Huang X . Automated design of ligands to polypharmacological profiles. Nature. 2012; 492(7428):215-20. PMC: 3653568. DOI: 10.1038/nature11691. View