Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for δ/μ Opioid Receptor Agonists and Neurokinin-1 Receptor Antagonists

Abstract

A series of bifunctional peptides that act as agonists for δ and μ opioid receptors with δ selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at δ/μ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 (5) and H-Tyr-DAla-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 (7) had excellent agonist activity for both δ opioid and μ opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

“…These data Using an Opioid Agonist/NK1 Antagonist for Chronic Pain suggest that targeting multiple molecular components may translate into safer and more efficacious pain therapeutics (Woodcock et al, 2007). We synthesized single compounds with distinct mechanisms of action: activate MOP/DOP while inhibiting endogenous SP at the NK 1 receptor (Yamamoto et al, 2007).…”

“…SP (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met; American Peptide, Sunnyvale, CA) was prepared as a solution in saline or 5% acetic acid/saline. TY027 and 125 I-TY027 were synthesized as described by Yamamoto et al (2007). Central dosing of TY027 ranged between 0.38 and 100.0 mg in 5 ml and 1 and 30 mg/kg (1 ml/kg volume) for experiments with systemic dosing.…”

“…We previously reported on peptidomimetic compounds that targeted MOP/DOP/NK 1 (Yamamoto et al, 2007) and characterized them in rodent models of pain (Largent-Milnes et al, 2010). The 39,59-bis(trifluoromethyl)-benzyl amide derivative of Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-Bn(CF 3 ) 2 (TY005) produced Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF 3 ) 2 (TY027), which has high affinity for the MOP, DOP, and NK 1 receptors; acts as an agonist at MOP and DOP and as an NK 1 antagonist; and is biologically stable (Yamamoto et al, 2007(Yamamoto et al, , 2009).…”

“…The 39,59-bis(trifluoromethyl)-benzyl amide derivative of Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-Bn(CF 3 ) 2 (TY005) produced Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF 3 ) 2 (TY027), which has high affinity for the MOP, DOP, and NK 1 receptors; acts as an agonist at MOP and DOP and as an NK 1 antagonist; and is biologically stable (Yamamoto et al, 2007(Yamamoto et al, , 2009). Here we demonstrate that TY027 is highly efficacious in rodent models of acute and neuropathic pain following multiple routes of administration while reducing adverse effects associated with opioid therapy, including antinociceptive tolerance, reward liability, gastrointestinal impairment, and physical dependence over a long duration.…”

Design of Multivalent Ligands that Cross the Blood Brain Barrier for the Treatment of Neuropathic Pain Without Toxicities

“…We also have examined second messenger cAMP activities and efficacies, as well as MVD and GP1 tissue assay activities (for 1 and 2 see references [2] and [3] for data). In all cases, the compounds are agonists at opioid receptors and antagonists at neurokinin 1 receptors (for 3, manuscript in preparation).…”