Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

Abstract

Acids 9 a–f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands

“…17,18 The large scale synthesis of functionalized Fentanyls—carboxyfentanyl ( 1a ), carboxymethylfentanyl ( 1b ) and fentanyl derivative ( 1c ) starting from 1-phenethyl- N -phenylpiperidin-4-amine 19 and appropriate acid anhydride was carefully worked out by us (Scheme 1). The three compounds differ essentially only in the construction of the side acid chain.…”

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

“…The first publication is probably that which described (4-piperidinyl)-2-indolinones (n = 1) and quinolinones (n = 2) ( 72 ). The synthetic approaches are very simple (Supplementary Information 18) [148–155]. The affinities are much less than that of fentanyl.…”

“…However biological assays data were not consistent with the results from the molecular modeling. The synthesized compounds did not show any significant analgesic activity in the entire series [155]. Another series of indolylpiperidines 87 and 89 have been synthesized from phenylhydrazones 86 and 88 obtained from the same 4-piperidylphenylhydrazines ( 81 ).…”

Twin and Triplet Drugs in Opioid Research

“…Twin drug 85 consisting of fentanyl (58) (m agonist) and indomethacin (84) (NSAID) pharmacophores [155], twin drugs 89 and 90 containing tramadol (86) (m agonist) and metoclopramide (87) (5-HT 4 agonist) or cisapride (88) (5-HT 4 agonist) pharmacophores [156], and twin drug 91 including fentanyl (58) (m agonist) and adenosine (92) (A 1 agonist) pharmacophores [157] were synthesized (Fig. 17).…”