Synthesis and biochemical studies of spirocyclic amino acids. II. Activity of 2-azaspiro[5.5]undecane-7-carboxylates as GABA-uptake inhibitors

W. Fleischhacker; S. Lauritz; E. Urban; P. Baumann; H. Bittiger

doi:10.1016/0223-5234(96)88288-2

Synthesis and biochemical studies of spirocyclic amino acids. II. Activity of 2-azaspiro[5.5]undecane-7-carboxylates as GABA-uptake inhibitors

W. Fleischhacker
, S. Lauritz
, E. Urban
, P. Baumann
, H. Bittiger

Department of Pharmaceutical Sciences

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Novel GABA analogous spirocyclic amino acids were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromopropyl lactones and arylalkylamines, spirocyclic hydroxyalkyl lactams were obtained, which were reduced by LiAlH₄ to yield spirocyclic hydroxymethyl piperidines. Oxidation by Jones' reagent followed by subsequent esterification gave the title compounds which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acids showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity on the length of the alkyl chain in N-arylalkyl substituents.

Original language	English
Pages (from-to)	707-713
Number of pages	7
Journal	European Journal of Medicinal Chemistry
Volume	30
Issue number	9
DOIs	https://doi.org/10.1016/0223-5234(96)88288-2
Publication status	Published - 1995

Funding

We thank W Robien, H Kalchhauser and H Kahlig (Institute of Organic Chemistry) for detection of 250 and 400 MHz tH-NMR spectra (apparatus supplied by Fonds zur Fiirdenmg der wissenschaftlichen Forschung, project 4009 and P6537C). S Lauritz thanks the Bundesministerium fiir Wissenschaft und Forschung for a scholarship.

Austrian Fields of Science 2012

301207 Pharmaceutical chemistry

Keywords

GABA uptake inhibitor
spirocyclic amino acid
structure-activity relationship

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10.1016/0223-5234(96)88288-2

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title = "Synthesis and biochemical studies of spirocyclic amino acids. II. Activity of 2-azaspiro[5.5]undecane-7-carboxylates as GABA-uptake inhibitors",

abstract = "Novel GABA analogous spirocyclic amino acids were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromopropyl lactones and arylalkylamines, spirocyclic hydroxyalkyl lactams were obtained, which were reduced by LiAlH4 to yield spirocyclic hydroxymethyl piperidines. Oxidation by Jones' reagent followed by subsequent esterification gave the title compounds which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acids showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity on the length of the alkyl chain in N-arylalkyl substituents.",

keywords = "GABA uptake inhibitor, spirocyclic amino acid, structure-activity relationship",

author = "W. Fleischhacker and S. Lauritz and E. Urban and P. Baumann and H. Bittiger",

note = "Funding Information: We thank W Robien, H Kalchhauser and H Kahlig (Institute of Organic Chemistry) for detection of 250 and 400 MHz tH-NMR spectra (apparatus supplied by Fonds zur Fiirdenmg der wissenschaftlichen Forschung, project 4009 and P6537C). S Lauritz thanks the Bundesministerium fiir Wissenschaft und Forschung for a scholarship.",

year = "1995",

doi = "10.1016/0223-5234(96)88288-2",

language = "English",

volume = "30",

pages = "707--713",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "ELSEVIER MASSON",

number = "9",

}

TY - JOUR

T1 - Synthesis and biochemical studies of spirocyclic amino acids. II. Activity of 2-azaspiro[5.5]undecane-7-carboxylates as GABA-uptake inhibitors

AU - Fleischhacker, W.

AU - Lauritz, S.

AU - Urban, E.

AU - Baumann, P.

AU - Bittiger, H.

N1 - Funding Information: We thank W Robien, H Kalchhauser and H Kahlig (Institute of Organic Chemistry) for detection of 250 and 400 MHz tH-NMR spectra (apparatus supplied by Fonds zur Fiirdenmg der wissenschaftlichen Forschung, project 4009 and P6537C). S Lauritz thanks the Bundesministerium fiir Wissenschaft und Forschung for a scholarship.

PY - 1995

Y1 - 1995

N2 - Novel GABA analogous spirocyclic amino acids were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromopropyl lactones and arylalkylamines, spirocyclic hydroxyalkyl lactams were obtained, which were reduced by LiAlH4 to yield spirocyclic hydroxymethyl piperidines. Oxidation by Jones' reagent followed by subsequent esterification gave the title compounds which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acids showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity on the length of the alkyl chain in N-arylalkyl substituents.

AB - Novel GABA analogous spirocyclic amino acids were prepared and investigated for interaction with GABA-A and GABA-B receptors as well as the GABA uptake system. Starting from known bromopropyl lactones and arylalkylamines, spirocyclic hydroxyalkyl lactams were obtained, which were reduced by LiAlH4 to yield spirocyclic hydroxymethyl piperidines. Oxidation by Jones' reagent followed by subsequent esterification gave the title compounds which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acids showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity on the length of the alkyl chain in N-arylalkyl substituents.

KW - GABA uptake inhibitor

KW - spirocyclic amino acid

KW - structure-activity relationship

UR - https://www.scopus.com/pages/publications/0029082519

U2 - 10.1016/0223-5234(96)88288-2

DO - 10.1016/0223-5234(96)88288-2

M3 - Article

AN - SCOPUS:0029082519

SN - 0223-5234

VL - 30

SP - 707

EP - 713

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 9

ER -

Synthesis and biochemical studies of spirocyclic amino acids. II. Activity of 2-azaspiro[5.5]undecane-7-carboxylates as GABA-uptake inhibitors

Abstract

Funding

Austrian Fields of Science 2012

Keywords

Access to Document

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