Amino Acids

, Volume 51, Issue 2, pp 255–261 | Cite as

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold

  • Kostiantyn P. Melnykov
  • Dmitriy M. Volochnyuk
  • Sergey V. Ryabukhin
  • Eduard B. Rusanov
  • Oleksandr O. GrygorenkoEmail author
Original Article


An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid—a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C1-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.


Conformational restriction Amino acids Bicyclic compounds Pyridine Hydrogenation GABA analogues 



The authors thank Prof. Andrey A. Tolmachev for his encouragement and support and Ms. Yuliya Kuchkovska for her help with preparation of Fig. 3.

Compliance with ethical standards 

Conflict of interest

The authors declare no conflict of interests.


The work was funded by Enamine Ltd.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Aceña JL, Sorochinsky AE, Soloshonok V (2014) Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations. Amino Acids 46:2047–2073. CrossRefPubMedGoogle Scholar
  2. Bordwell FG (1988) Equilibrium acidities in dimethyl sulfoxide solution. Acc Chem Res 21:456–463. CrossRefGoogle Scholar
  3. Cativiela C, Ordóñez M (2009) Recent progress on the stereoselective synthesis of cyclic quaternary alpha-amino acids. Tetrahedron Asymmetry 20:1–63. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chebib M, Allan RD, Duke RK, Johnston GAR (2001) The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABAC receptors. Eur J Pharmacol 430:185–192. CrossRefPubMedGoogle Scholar
  5. Crittenden DL, Jordan MJT, Chebib M, Crittenden DL, Park A, Qiu J, Silverman RB, Duke RK, Johnston GAR (2006) Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors. Bioorg Med Chem 14:447–455. CrossRefPubMedGoogle Scholar
  6. Fang Z, Song Y, Zhan P, Zhang Q, Liu X (2014) Conformational restriction: an effective tactic in ‘follow-on’-based drug discovery. Future Med Chem 6:885–901. CrossRefPubMedGoogle Scholar
  7. Fülöp F, Martinek TA, Tóth GK (2006) Application of alicyclic β-amino acids in peptide chemistry. Chem Soc Rev 2006:323–334. CrossRefGoogle Scholar
  8. Gellman SH (1998) Foldamers: a manifesto. Acc Chem Res 31:173–180. CrossRefGoogle Scholar
  9. Grimm JS, Maryanoff CA, Patel M, Palmer DC, Sorgi KL, Stefanick S, Webster RRH, Zhang X (2002) Reaction safety: a critical parameter in the development of a scalable synthesis of 2,3-bis-chloromethylpyridine hydrochloride. Org Proc Res Dev 6:938–942. CrossRefGoogle Scholar
  10. Grygorenko OO, Babenko P, Volochnyuk DM, Raievskyi O, Komarov IV (2016) Following Ramachandran: exit vector plots (EVP) as a tool to navigate chemical space covered by 3D bifunctional scaffolds. The case of cycloalkanes. RSC Adv 6:17595–17605. CrossRefGoogle Scholar
  11. Grygorenko OO, Demenko D, Volochnyuk DM, Komarov IV (2018) Following Ramachandran 2: exit vector plot (EVP) analysis of disubstituted saturated rings. New J Chem 42:8355–8365. CrossRefGoogle Scholar
  12. Guthikonda RN, Shah SK, Pacholok SG, Humes JL, Mumford RA, Grant SK, Chabin RM, Green BG, Tsou N, Ball R, Fletcher DS, Luell S, Euan MacIntyre D, Maccoss M (2005) Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase. Bioorg Med Chem Lett 15:1997–2001. CrossRefPubMedGoogle Scholar
  13. Janecka A, Kruszynski R (2005) Conformationally restricted peptides as tools in opioid receptor studies. Curr Med Chem 12:471–481. CrossRefPubMedGoogle Scholar
  14. Kaneda M, Nakamura S, Iitaka Y (1980) Absolute structure of amidinomycin. J Antibiot 33:778–780. CrossRefPubMedGoogle Scholar
  15. Kiss L, Cherepanova M, Fülöp F (2015) Recent advances in the stereoselective syntheses of acyclic disubstituted β2,3-amino acids. Tetrahedron 71:2049–2069. CrossRefGoogle Scholar
  16. Kobayashi T, Suemasa A, Igawa A, Ide S, Fukuda H, Abe H, Arisawa M, Minami M, Shuto S (2014) Conformationally restricted gaba with bicyclo[3.1.0]hexane backbone as the first highly selective BGT-1 inhibitor. ACS Med Chem Lett 5:889–893. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Komarov IV, Grigorenko AO, Turov AV, Khilya VP (2004) Conformationally rigid cyclic α-amino acids in the design of peptidomimetics peptide models and biologically active compounds. Russ Chem Rev 73:785–810. CrossRefGoogle Scholar
  18. Mann A (2008) Conformational restriction and/or steric hindrance in medicinal chemistry. In: Wermuth CG (ed) Practice of medicinal chemistry, 3rd edn. Academic Press/Elsevier, Amsterdam, pp 363–379. ISBN 0123741947CrossRefGoogle Scholar
  19. Mora AJ, Avila EE, Delgado GE, Fitch AN, Brunelli M (2005) Temperature effects on the hydrogen-bond patterns in 4-piperidine-carboxylic acid. Acta Cryst Sect B 61:96–102. CrossRefGoogle Scholar
  20. Mortensen M, Kristiansen U, Ebert B, Frølund B, Krogsgaard-Larsen P, Smart TG (2004) Activation of single heteromeric GABAA receptor ion channels by full and partial agonists. J Physiol 557:389–413. CrossRefPubMedGoogle Scholar
  21. Ordóñez M, Cativiela C (2007) Stereoselective synthesis of γ-amino acids. Tetrahedron Asymmetry 18:3–99. CrossRefGoogle Scholar
  22. Pingsterhaus JM, Qiu J, Silverman RB (1999) Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase. J Med Chem 42:4725–4728. CrossRefPubMedGoogle Scholar
  23. Soloshonok VA (2002) Highly diastereoselective Michael addition reactions between nucleophilic glycine equivalents and β-substituted-α, β-unsaturated carboxylic acid derivatives a general approach to the stereochemically defined and sterically χ-constrained α-amino acids. Curr Org Chem 6:341–364. CrossRefGoogle Scholar
  24. Sorochinsky A, Aceña J, Moriwaki H, Sato T, Soloshonok V (2013a) Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; part 1: alkyl halide alkylations. Amino Acids 45:691–718. CrossRefPubMedGoogle Scholar
  25. Sorochinsky A, Aceña J, Moriwaki H, Sato T, Soloshonok V (2013b) Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids. Amino Acids 45:1017–1033. CrossRefPubMedGoogle Scholar
  26. Szabo CM, Martin MB, Oldfield E (2002) An investigation of bone resorption and Dictyostelium discoideum growth inhibition by bisphosphonate drugs. J Med Chem 45:2894–2903. CrossRefPubMedGoogle Scholar
  27. Trabocchi A, Scarpi D, Guarna A (2008) Structural diversity of bicyclic amino acids. Amino Acids 34:1–24. CrossRefPubMedGoogle Scholar
  28. Vagner J, Qu H, Hruby V (2008) Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol 12:292–296. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Van Bever WFM, Knaeps AG, Willems JJM, Hermans BKF, Janssen PAJ (1973) Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 16:394–397. CrossRefPubMedGoogle Scholar
  30. Wang Y, Song X, Wang J, Moriwaki H, Soloshonok V, Liu H (2017) Recent approaches for asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes. Amino Acids 49:1487–1520. CrossRefPubMedGoogle Scholar
  31. Witiak DT, Patch RJ, Enna SJ, Fung YK (1986) Stereoselective syntheses of the trans-decahydroquinoline-5-carboxylic acid epimers. Diastereomeric zwitterionic probes of γ-aminobutyric acid-related biological properties in vitro and in vivo. J Med Chem 29:1–8. CrossRefPubMedGoogle Scholar
  32. Woll MG, Lai JR, Guzei IA, Taylor SJC, Smith MEB, Gellman SH (2001) Parallel sheet secondary structure in γ-peptides. J Am Chem Soc 123:11077–11078. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Kostiantyn P. Melnykov
    • 1
    • 2
  • Dmitriy M. Volochnyuk
    • 3
  • Sergey V. Ryabukhin
    • 2
  • Eduard B. Rusanov
    • 3
  • Oleksandr O. Grygorenko
    • 1
    • 2
    Email author
  1. 1.Enamine Ltd.KyivUkraine
  2. 2.National Taras Shevchenko University of KyivKyivUkraine
  3. 3.Institute of Organic ChemistryNational Academy of Sciences of UkraineKyivUkraine

Personalised recommendations