Synthesis of 6‐Amino Acid Substituted Derivatives of the Highly Potent Analgesic 14‐O‐Methyloxymorphone

Abstract

The novel morphinans 13 ± 18, which carry amino acid substituents at C(6), with potentially limited access to the central nervous system were prepared in two steps from 14-O-methyloxymorphone (5). Reductive amination with amino acid tert-butyl esters gave compounds 7 ± 12, which were hydrolyzed with tetrafluoroboric acid. Structure elucidation (including X-ray analysis), preliminary m-opioid receptor binding studies, and calculations of pharmacokinetic parameters were carried out.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…In a model of neuropathic pain, systemically (subcutaneously) applied loperamide reversed mechanical allodynia by activation of peripheral -receptors (Guan et al, 2008). Peripheral restriction was further pursued with arylacetamide morphinan-based [nalfurafine, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid (DiPOA)] and with peptidic compounds [Tyr-Arg-Phe-Lys-NH 2 (DALDA)] (for reviews, see Schü tz et al, 2003;DeHavenHudkins and Dolle, 2004;Chu et al, 2007). Some of these were subsequently abandoned, mostly because the chemical addition of hydrophilic residues led to reduced affinity at opioid receptors or because higher doses were able to penetrate the blood-brain barrier.…”

Synthesis and Pharmacological Activities of 6-Glycine Substituted 14-Phenylpropoxymorphinans, a Novel Class of Opioids with High Opioid Receptor Affinities and Antinociceptive Potencies

“…(29) These compounds displayed high affinities at the μ opioid receptor and showed potent agonism. (30) A number of pharmacological studies reported that amino acid substitution in position 6 of 14- O -methyloxymorphone affords derivatives that produce potent antinociceptive actions in rodent models of acute nociception, inflammatory, visceral, and neuropathic pain.…”

Synthesis, Pharmacology, and Molecular Docking Studies on 6-Desoxo-N-methylmorphinans as Potent μ-Opioid Receptor Agonists

“… 11 We and others have reported on the incorporation of amino acid residues at position 6 of N -methylmorphinan-6-ones. 12 The 6-amino acid zwitterionic conjugates of 2 were established as MOR agonists inducing potent and long-lasting peripherally mediated antinociceptive effects after systemic administration. 4 , 5a , 13 The 6β-glycine substituted derivative of 2 was equipotent to fentanyl in the tail-flick assay in rats, acting via activation of peripherally located opioid receptors.…”