Chiral Effect of a Phe Residue in Position 3 of the Dmt¹‑l(or d)‑Tic² Analogues on Opioid Functional Activities

In this letter, we describe a structure–activity relationships study, specifically related to the chirality of third amino acid residue in our H-Dmt-l­(or d)-Tic analogues, of which C-terminus is attached to a piperidinyl moiety. Observed selectivities and functional activities of these analogues demonstrated that the chiralities of the second and third position residues are crucial for determining whether these ligands act as antagonists or agonists at the δ opioid receptor, but not at the μ opioid receptor

<i>cis</i>-4-Amino‑l‑proline Residue As a Scaffold for the Synthesis of Cyclic and Linear Endomorphin‑2 Analogues: Part 2

Recently, we reported synthesis and activity of a constrained cyclic analogue of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH₂) and related linear models containing the <i>cis</i>-4-amino-l-proline (cAmp) in place of native Pro². In the present article, the adopted rationale is the possible modulation of the receptor affinity of the cAmp containing EM-2 analogues by assigning a different stereochemistry to the Phe³ and Phe⁴ residues present in the ring. Thus, eight more analogues with different absolute configuration at the chiral center of the aromatic residues in positions 3 and 4 have been synthesized and their opioid activity examined. The stereochemical change at the α-carbon atoms leads to a meaningful enhancement of the affinity and activity toward μ opioid receptors with respect to the prototype compound <b>9</b>: e.g., <b>9a</b>, <i>K</i>_<i>i</i>^μ = 63 nM, GPI (IC₅₀) = 480 nM; <b>9b</b>, <i>K</i>_<i>i</i>^μ = 38 nM, GPI (IC₅₀) = 330 nM

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 <i>N</i>MePhe at the fourth position (ligand <b>3</b>: H-Dmt-d-Ala-Gly-<i>NMe</i>Phe-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-<i>F</i>) at the fourth position (ligand <b>5</b>: 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 <b>3</b> and <b>5</b> with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands <b>3</b>, <b>5</b>, and <b>7</b> (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 (<b>3</b>: <i>T</i>_1/2 > 24 h; <b>5</b>: <i>T</i>_1/2 ≈ 6 h; <b>7</b>: <i>T</i>_1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity

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 <i>N</i>MePhe at the fourth position (ligand <b>3</b>: H-Dmt-d-Ala-Gly-<i>NMe</i>Phe-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-<i>F</i>) at the fourth position (ligand <b>5</b>: 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 <b>3</b> and <b>5</b> with excellent in vitro biological activity profiles. Metabolic stability studies in rat plasma with ligands <b>3</b>, <b>5</b>, and <b>7</b> (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 (<b>3</b>: <i>T</i>_1/2 > 24 h; <b>5</b>: <i>T</i>_1/2 ≈ 6 h; <b>7</b>: <i>T</i>_1/2 > 2 h). Preliminary in vivo studies with these two ligands have shown promising antinociceptive activity

Structure–Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the κ Opioid Receptor

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure–activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg⁷ residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg⁷]­Dyn A analogues found that Arg⁷ is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg⁷]­Dyn A­(1–9)-NH₂ is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, <b>14</b>, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse