Discovery of Novel Multifunctional Ligands with µ/δ Opioid Agonist/Neurokinin-1 (NK1) Antagonist Activities for the Treatment of Pain.

Multifunctional ligands with agonist bioactivities at µ/δ opioid receptors (MOR/DOR) and antagonist bioactivity at the neurokinin-1 receptor (NK1R) have been designed and synthesized. These peptide-based ligands are anticipated to produce better biological profiles (e.g., higher analgesic effect with significantly less adverse side effects) compared to those of existing drugs and to deliver better synergistic effects than coadministration of a mixture of multiple drugs. A systematic structure-activity relationship (SAR) study has been conducted to find multifunctional ligands with desired activities at three receptors. It has been found that introduction of Dmt (2,6-dimethyl-tyrosine) at the first position and NMePhe at the fourth position (ligand 3: H-Dmt-d-Ala-Gly-NMePhe-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) displays binding as well as functional selectivity for MOR over DOR while maintaining efficacy, potency, and antagonist activity at the NK1R. Dmt at the first position with Phe(4-F) at the fourth position (ligand 5: H-Dmt-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) exhibits balanced binding affinities at MOR and DOR though it has higher agonist activity at DOR over MOR. This study has led to the discovery of several novel ligands including 3 and 5 with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands 3, 5, and 7 (H-Tyr-d-Ala-Gly-Phe(4-F)-Pro-Leu-Trp-NH-Bn(3',5'-(CF3)2)) showed that their stability depends on modifications at the first and fourth positions (3: T1/2 > 24 h; 5: T1/2 ≈ 6 h; 7: T1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity.

Investigational peptide and peptidomimetic µ and δ opioid receptor agonists in the relief of pain.

INTRODUCTION: Current methods for treating prolonged and neuropathic pain are inadequate and lead to toxicities that greatly diminish quality of life. Therefore, new approaches to the treatment of pain states are needed to address these problems. AREAS COVERED: The review primarily reviews approaches that have been taken in the peer-reviewed literature of multivalent ligands that interact with both µ and δ opioid receptors as agonists, and in some cases, also with pharmacophores for antagonist ligands that interact with other receptors as antagonists to block pain. EXPERT OPINION: Although there are a number of drugs currently on the market for the treatment of pain; none of them are 100% successful. In the authors' opinion, it is clear that new directions and modalities are needed to better address the treatment of prolonged and neuropathic pain; one drug or class clearly is not the answer for all pain therapy. Undoubtedly, there are many different phenotypes of prolonged and neuropathic pain and this should be one avenue to further develop appropriate therapies.

Asymmetric syntheses of (-)-enterolactone and (7'R)-7'-hydroxyenterolactone via organocatalyzed aldol reaction.

Short syntheses of (-)-enterolactone (1a) and (7'R)-7'-hydroxyenterolactone (1b) have been achieved utilizing organocatalyzed asymmetric cross-aldol reaction of aldehydes 2 and 3 and base-mediated alkylation of lactones 5 and 4.

Organocatalytic and enantioselective synthesis of beta-(hydroxyalkyl)-gamma-butyrolactones.

Organocatalytic cross-aldol reaction of methyl 4-oxobutyrate (2) and a variety of aldehydes 3 followed by reduction with NaBH(4) has provided a one-pot, general and efficient method for the synthesis of 4-(hydroxyalkyl)-gamma-butyrolactones 1 with high diastereo-(dr > 24:1) and enantioselectivity (ee > 99%).

Asymmetric aldol reactions under normal and inverse addition modes of the reagents.

Both syn- and anti-aldol products can be obtained from common reactants by simply changing their addition sequence.