Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel σ1 receptor ligands.

Abstract

Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the σ1 affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ1 affinity. These results fit nicely to the reported σ1 pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ8,7-isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, Ki(σ1)=0.86nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ1 agonistic activity of (S)-28b. Even at a dose of 100mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine.

• Authors: Lena Fanter, Christoph Müller, Dirk Schepmann, Franz Bracher, Bernhard Wünsch
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 25 Issue 17 Pg. 4778-4799 (09 01 2017) ISSN: 1464-3391 [Electronic] England
• PMID: 28764962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• 1,4-diazepane
• Azepines
• Enzyme Inhibitors
• Ligands
• Receptors, sigma
• Cholesterol

Topics

• Animals
• Azepines (chemistry, metabolism, pharmacology, toxicity)
• Cholesterol (biosynthesis)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (chemical synthesis, metabolism, pharmacology, toxicity)
• Guinea Pigs
• Kinetics
• Ligands
• Male
• Muscle Contraction (drug effects)
• Protein Binding
• Receptors, sigma (agonists, metabolism)
• Stereoisomerism
• Structure-Activity Relationship
• Yeasts (drug effects, metabolism)