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GABA Analogues Derived from 4-Aminocyclopent-1-enecarboxylic Acid

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Abstract

The incorporation of extra binding groups onto known ligands is a powerful tool for the development of more potent and selective agents at target sites such as the GABA receptors. In the present work we have attempted to build on the activity of the know potent GABAA agonist 4-ACP-3-CA and its cis and trans saturated analogues CACP and TACP. We have investigated reactions to add thiol substituents to the α,β-unsaturated system of 4-ACP-3-CA. The reaction was successful with a limited number of thiols but gave products of mixed stereochemistry. The resultant thioether amino acids were screened for activity at human recombinant α1β2 γ2L GABAA receptors. The most interesting derivative was the benzylthioether which acted as an antagonist with an IC50 of 42 μM for the inhibition of a GABA EC50 dose (50 μM). This study has shown that GABA analogues derived by thiol addition to 4-aminocyclopent-1-enecarboxylic acid display interesting antagonist activity at the α1β2γ2L GABAA receptor.

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References

  1. Allan RD, Dickenson HW, Fong J (1986) Structure-activity studies on the activity of a series of cyclopentane GABA analogues on GABAA receptors and GABA uptake. Eur J Pharmacol 122:339–348. doi:10.1016/0014-2999(86)90414-0

    Article  PubMed  CAS  Google Scholar 

  2. Krogsgaard-Larsen P, Frølund B, Liljefors T (2002) Specific GABAA agonists and partial agonists. Chem Rec 2:419–430. doi:10.1002/tcr.10040

    Article  PubMed  CAS  Google Scholar 

  3. Frølund B, Jensen LS, Storustovu SI, Stensbol TB, Ebert B, Kehler J, Krogsgaard-Larsen P, Liljefors T (2007) 4-Aryl-5-(4-piperidyl)-3-isoxazol GABAA antagonists: synthesis, pharmacology and structure-activity relationships. J Med Chem 50:1988–1992. doi:10.1021/jm070038n

    Article  PubMed  Google Scholar 

  4. Allan RD, Fong J (1986) Synthesis of analogues of GABA. XV. Preparation and resolution of some potent cyclopentene and cyclopentane derivatives. Aust J Chem 39:855–864

    CAS  Google Scholar 

  5. Chebib M, Duke RK, Allan RD, Johnston GAR (2001) The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABAC receptors. Eur J Pharmacol 430:185–192. doi:10.1016/S0014-2999(01)01390-5

    Article  PubMed  CAS  Google Scholar 

  6. Johnston GAR, Curtis DR, Game CJA, McCulloch RM, Twitchin B (1976) cis- and trans-3-aminocyclopentane-1-carboxylic acid as GABA analogues of restricted conformation. Proc Aust Physiol Pharmacol Soc 7:32

    Google Scholar 

  7. Abdel-Halim H, Hanrahan JR, Hibbs DE, Johnston GAR, Chebib M (2008) A molecular basis for agonist and antagonist actions at GABA-C receptors. Chem Biol Drug Des 71:306–327. doi:10.1111/j.1747-0285.2008.00642.x

    Article  PubMed  CAS  Google Scholar 

  8. Nishimura K, Ono M, Nagaoka Y, Tomioka K (1997) Steric tuning of reactivity and enantioselectivity in addition of thiophenol to enoates catalyzed by an external chiral ligand. J Am Chem Soc 119:12974–12975. doi:10.1021/ja9729950

    Article  CAS  Google Scholar 

  9. Crane SN, Black WC, Palmer JT, Davis DE, Setti E, Robichaud J, Paquet J, Oballa RM, Bayly CI, McKay DJ, Somoza JR, Chauret N, Seto C, Scheigetz J, Wesolowski G, Masse F, Desmarais S, Ouellet M (2006) Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. J Med Chem 49:1066–1079. doi:10.1021/jm051059p

    Article  PubMed  CAS  Google Scholar 

  10. Cocuzsa AJ, Boawell GA (1985) Cyclobutanone analogues of beta-lactam antibiotics: synthesis of N-acetyldeazathienamycin. Tetrahedron Lett 26(44):5363–5366. doi:10.1016/S0040-4039(00)98208-X

    Article  Google Scholar 

  11. Kumar RJ, Chebib M, Hibbs DE, Kim H-L, Johnston GAR, Salam NK, Hanrahan JR (2008) Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure activity relationships. J Med Chem 51:3825–3840. doi:10.1021/jm7015842

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Steven Devenish, Tim Bakas, Chiu Chin Ng, and Kelly Skilbeck for their technical assistance.

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Authors and Affiliations

  1. The Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, The University of Sydney, Sydney, NSW, 2006, Australia

    Katherine E. S. Locock, Graham A. R. Johnston & Robin D. Allan

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  1. Katherine E. S. Locock
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  2. Graham A. R. Johnston
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  3. Robin D. Allan
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Corresponding author

Correspondence to Robin D. Allan.

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Special issue article in honour of Dr. Graham Johnston.

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Locock, K.E.S., Johnston, G.A.R. & Allan, R.D. GABA Analogues Derived from 4-Aminocyclopent-1-enecarboxylic Acid. Neurochem Res 34, 1698–1703 (2009). https://doi.org/10.1007/s11064-009-0005-x

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  • DOI: https://doi.org/10.1007/s11064-009-0005-x

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