Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic Acid-I, a potent mGluR agonist

Alan P. Kozikowski, Darryl Steensma, Gian Luca Araldi, Werner Tückmantel, Shaomeng Wang, Sergey Pshenichkin, Elena Surina, Jarda T. Wroblewski

Research output: Contribution to journalArticle

Abstract

To better characterize the roles of metabotropic glutamate receptors (mGluRs) in physiological and pathophysiological processes, there is an important need to learn more about the structural features relevant to the design of novel, high-affinity ligands that are family and subtype specific. To date, many of the biological studies that have been conducted in the area of mGluR research have made use of the agonist (1S,3R)-ACPD. This compound has been shown to act as an agonist at both the group I and group II receptors while showing little selectivity among the four subtypes belonging to these two groups. Moreover, (1S,3S)-ACPD, the cis isomer, shows negligible activity at group I receptors and is a good agonist of mGluR2. Since ACPD is itself somewhat flexible, with four distinctive conformations being identified from molecular modeling studies for the trans isomer and five conformations for the cis isomer, we believed that it would be of interest to examine the activity of an ACPD analogue that has been constrained through the introduction of a single carbon atom bridge. Accordingly, we have prepared an aminobicyclo[2.1.1]hexanedicarboxylic acid (ABHxD-I) analogue of ACPD. The synthesis of this compound was accomplished by use of an intramolecular [2 + 2] photocycloaddition reaction, in which four distinct isomers were isolated. Of these four compounds, only a single isomer, ABHxD- I (6a), was found to be a potent agonist of the mGluRs. This compound, which expresses the fully extended glutamate conformation, was found to be more potent than ACPD at all six of the eight mGluR subtypes that were investigated and to be comparable to or more potent than the endogenous ligand, glutamate, for these receptors. Interestingly, despite its fixed conformation, ABHxD-I, like glutamate, shows little subtype selectivity. Through modeling studies of ABHxD-I (6a), ABHD-VI, LY354740, (1S,3R)-ACPD, (1S,3S)-ACPD, and L-glutamate, we conclude that the aa conformation of L- glutamate is the active conformation for both group I and group II mGluRs. Moreover, the modeling-based comparisons of these ligands suggest that the selectivity exhibited by LY354740 between the group I and group II mGluRs is not a consequence of different conformations of L-glutamate being required for recognition at these mGluRs but rather is related to certain structural elements within certain regions having a very different impact on the group I and group II mGluR activity. The enhanced potency of ABHxD-I relative to trans-ACPD commends it as a useful starting point in the design of subtype selective mGluR ligands.

Original languageEnglish (US)
Pages (from-to)1641-1650
Number of pages10
JournalJournal of medicinal chemistry
Volume41
Issue number10
DOIs
StatePublished - May 7 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic Acid-I, a potent mGluR agonist'. Together they form a unique fingerprint.

  • Cite this

    Kozikowski, A. P., Steensma, D., Araldi, G. L., Tückmantel, W., Wang, S., Pshenichkin, S., Surina, E., & Wroblewski, J. T. (1998). Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic Acid-I, a potent mGluR agonist. Journal of medicinal chemistry, 41(10), 1641-1650. https://doi.org/10.1021/jm970719q