Development of Novel Enkephalin Analogues that Have Enhanced Opioid Activities at Both μ and δ Opioid Receptors

Abstract

Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

“…Obtained compounds showed broad (47 nM to 76 μM) and μ-selective activities. For the synthesis of possible μ/δ compounds (Figure 19) amine ( 5 ) was coupled with protected phenylalanine or its p-F(Cl)-substituted analogs to give ( 123 ), which after deprotection were stepwise transferred to desired bivalent ligands ( 125 ) [193,194]. Compounds with X = H and D-Yyy-Ala showed potent binding affinities (0.4 nM) at μ and δreceptors with increased hydrophobicity (aLogP = 2.96), and potent agonist activities in the MVD (1.8 nM) and GPI (8.5 nM) assays [193].…”

“…For the synthesis of possible μ/δ compounds (Figure 19) amine ( 5 ) was coupled with protected phenylalanine or its p-F(Cl)-substituted analogs to give ( 123 ), which after deprotection were stepwise transferred to desired bivalent ligands ( 125 ) [193,194]. Compounds with X = H and D-Yyy-Ala showed potent binding affinities (0.4 nM) at μ and δreceptors with increased hydrophobicity (aLogP = 2.96), and potent agonist activities in the MVD (1.8 nM) and GPI (8.5 nM) assays [193]. Ligands with X = F, D-Yyy-Nle showed potent subnanomolar opioid agonist activity (IC 50 values of 0.37 and 0.26 nM in the MVD and GPI assays, respectively) with excellent efficacy (EC 50 = 0.07 nM, E max = 48% at hDOR; EC 50 = 0.29 nM, E max = 98% at rMOR) at both receptors.…”

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

“…The co-administration of opioid agonists and a type of antidepressants, SSRIs, is expected to give a synergistic effect 17,18 and we herein set out to design an strategy to this co-administration, developing bifunctional ligands, an approach that has proven successful in the past for increasing potency and selectivity of many drugs. The drug design was based on bifunctional ligands interacting with two targets in a single molecule by combining two pharmacophores; opioid and SSRIs (Figure 1).…”

“…The SSRIs pharmacophore desmethylescitalopram 1 was combined with an opioid pharmacophore so that the designed ligands maintain the topographical structures of both pharmacophores, bearing in mind the development of previously designed μ-opioid selective 4-anilidopiperidine, and N -phenyl- N -piperidin-4-yl-propionamide analogues. 18 For the opioid agonist activity, enkephalin-like tetrapeptide structures (H-Tyr- D -Ala-Gly-Phe-) has been selected and modified. For the SSRIs activity, escitalopram, one of the most efficient SSRIs drug, has been selected and modified to get compound 1 .…”

Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

“…enkephalin-analogs linked to a fentanyl unit (e.g. structure 3 )] 14,15. In specific cases, improved pharmacodynamic and pharmacokinetic properties like enhanced affinity, increased activity, relative to ‘the golden standard’ morphine, and high metabolic stability were observed 3,6.…”