136109-04-1Relevant academic research and scientific papers
Stereoselective Synthesis of 6-Substituted Decahydroisoquinoline-3-carboxylates: Intermediates for the Preparation of Conformationally Constrained Acidic Amino Acids
Ornstein, Paul L.,Augenstein, Nancy K.,Arnold, M. Brian
, p. 7862 - 7869 (2007/10/02)
In this article we describe the stereoselective preparation of two 6-(hydroxymethyl) substituted decahydroisoquinoline-3-carboxylates, which are useful in the synthesis of a number of excitatory amino acid antagonists, e.g., (-)-1a (LY235959), (-)-2a (LY202157) and (-)-3a (LY293558).For example, the known ketone 4 was converted to either the (3SR,4aRS,6SR,8aRS)-alcohol 18 or the (3SR,4aRS,6RS,8aRS)-alcohol 21, the former via a stereoselective hydroboration reaction, the latter via a stereoselective enol ether hydrolysis followed by reduction.These C-6 epimeric alcohols were easily converted to a number of useful intermediates, e.g., aldehydes, bromides and iodides.If we used resolved keone 4, then these intermediates could be obtained in optically active form.In either racemic or non-racemic form, these intermediates provided access to a number of diastereomerically pure amino acids that were difficult to obtain by earlier routes.
6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists
Ornstein,Schoepp,Arnold,Augenstein,Lodge,Millar,Chambers,Campbell,Paschal,Zimmerman,Leander
, p. 3547 - 3560 (2007/10/02)
We have prepared a series of 6-substituted decahydroisoquinoline-3- carboxylic acids, and structurally similar analogs, as potential N-methyl-D- aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate- mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([3H]CGS19755, [3H]AMPA, and [3H]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [3H]CGS19755 binding with IC50s of 55 ± 14 and 856 ± 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 ± 0.01 and 1.39 ± 0.29 μM, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.
