Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist

Ana Belén Bueno, Iván Collado, Alfonso De Dios, Carmen Domínguez, José Alfredo Martín, Luisa M. Martín, María Angeles Martínez-Grau, Carlos Montero, Concepción Pedregal, John Catlow, D. Scott Coffey, Michael P. Clay, Anne H. Dantzig, Terry Lindstrom, James A. Monn, Haiyan Jiang, Darryle D. Schoepp, Robert Stratford Jr., Linda B. Tabas, Joseph P. TizzanoRebecca A. Wright, Marc F. Herin

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

Original languageEnglish (US)
Pages (from-to)5305-5320
Number of pages16
JournalJournal of Medicinal Chemistry
Volume48
Issue number16
DOIs
StatePublished - Aug 11 2005
Externally publishedYes

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eglumetad
Excitatory Amino Acid Agonists
Metabotropic Glutamate Receptors
Dipeptides
Prodrugs
Fear
Amino Acids
Active Biological Transport
Intestinal Absorption
Anxiety Disorders
Pharmaceutical Preparations
Biological Availability
Oral Administration
Anxiety
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. / Bueno, Ana Belén; Collado, Iván; De Dios, Alfonso; Domínguez, Carmen; Martín, José Alfredo; Martín, Luisa M.; Martínez-Grau, María Angeles; Montero, Carlos; Pedregal, Concepción; Catlow, John; Coffey, D. Scott; Clay, Michael P.; Dantzig, Anne H.; Lindstrom, Terry; Monn, James A.; Jiang, Haiyan; Schoepp, Darryle D.; Stratford Jr., Robert; Tabas, Linda B.; Tizzano, Joseph P.; Wright, Rebecca A.; Herin, Marc F.

In: Journal of Medicinal Chemistry, Vol. 48, No. 16, 11.08.2005, p. 5305-5320.

Research output: Contribution to journalArticle

Bueno, AB, Collado, I, De Dios, A, Domínguez, C, Martín, JA, Martín, LM, Martínez-Grau, MA, Montero, C, Pedregal, C, Catlow, J, Coffey, DS, Clay, MP, Dantzig, AH, Lindstrom, T, Monn, JA, Jiang, H, Schoepp, DD, Stratford Jr., R, Tabas, LB, Tizzano, JP, Wright, RA & Herin, MF 2005, 'Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist', Journal of Medicinal Chemistry, vol. 48, no. 16, pp. 5305-5320. https://doi.org/10.1021/jm050235r
Bueno, Ana Belén ; Collado, Iván ; De Dios, Alfonso ; Domínguez, Carmen ; Martín, José Alfredo ; Martín, Luisa M. ; Martínez-Grau, María Angeles ; Montero, Carlos ; Pedregal, Concepción ; Catlow, John ; Coffey, D. Scott ; Clay, Michael P. ; Dantzig, Anne H. ; Lindstrom, Terry ; Monn, James A. ; Jiang, Haiyan ; Schoepp, Darryle D. ; Stratford Jr., Robert ; Tabas, Linda B. ; Tizzano, Joseph P. ; Wright, Rebecca A. ; Herin, Marc F. / Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 16. pp. 5305-5320.
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T1 - Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist

AU - Bueno, Ana Belén

AU - Collado, Iván

AU - De Dios, Alfonso

AU - Domínguez, Carmen

AU - Martín, José Alfredo

AU - Martín, Luisa M.

AU - Martínez-Grau, María Angeles

AU - Montero, Carlos

AU - Pedregal, Concepción

AU - Catlow, John

AU - Coffey, D. Scott

AU - Clay, Michael P.

AU - Dantzig, Anne H.

AU - Lindstrom, Terry

AU - Monn, James A.

AU - Jiang, Haiyan

AU - Schoepp, Darryle D.

AU - Stratford Jr., Robert

AU - Tabas, Linda B.

AU - Tizzano, Joseph P.

AU - Wright, Rebecca A.

AU - Herin, Marc F.

PY - 2005/8/11

Y1 - 2005/8/11

N2 - (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

AB - (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

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