Synthesis and Biological Evaluation of 14‐Alkoxymorphinans. Part 8. 14‐methoxymetopon, an extremely potent opioid agonist

Abstract

14-Methoxymetopon ( = 5,1443 -dimethyloxymorphone; 4) and 14-ethoxymetopon (5) were synthesized from 14-hydroxy-5-methylcodeinone (6). In the AcOH-writhing test in mice, compound 4 was found to be ca. 20000 times more potent than morphine.Introduction. -5-Methyloxymorphone ( = 14-hydroxymetopon; 1) was found to possess slightly less opioid-agonist properties than oxymorphone (2) [2]. When compared to the highly potent opioid agonist 14-0-methyloxymorphone (3) [3], compound 1 CH3 '"/ R2 1 R'=R3=H,R2=CH, 2 R' = R2 = R3 = H (oxymorphone) 3 R'=CH,,R2=R3=H 4 R'=R2=CH3,R3=H 5 R' = C, H, , R2= CH,, R3 = H 9 R'=R2=R3=CH3 10 R'=C,H,, RZ=R3=CH3 12 R'=C2H,,R2=R3=H N /cH3 6 R' = H, R2 = CH, 7 R'=R2=CH3 11 R'=CH,, R 2 = H 8 R' = C2H,, R~ = CH,showed ca. 1/100th the antinociceptive potency in the AcOH-writhing test [2]. It was of interest if a 14-0-alkylation of 1 (to give compounds 4 and 5) would enhance its opioid agonist properties to a similar extent as a 14-0-alkylation of oxymorphone into compound 3 could [3]. I)part 7: [I].

Peripherally Mediated Antinociception of the μ-Opioid Receptor Agonist 2-[(4,5α-Epoxy-3-hydroxy-14β-methoxy-17-methylmorphinan-6β-yl)amino]acetic Acid (HS-731) after Subcutaneous and Oral Administration in Rats with Carrageenan-Induced Hindpaw Inflammation

“…Administration of a low dose (20 g/kg s.c.) of 14-methoxymetopon produced a significant attenuation of nociceptive behavior in inflamed paws, demonstrated by increased HWL on application of pressure or heat, showing similar potency to morphine (2 mg/kg s.c.). The profile of the antinociceptive activity of 14-methoxymetopon identified in this study confirms previous reports on acute nociception using different pain stimuli and animal species (rat and mouse) (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003). The analgesic effects of 14-methoxymetopon were reversed by naloxone and naltrexone, two opioid antagonists that readily cross the blood-brain barrier (Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003), indicating that 14-methoxymetopon has central actions.…”

“…HS-731 (Schü tz et al, 2003) and 14-methoxymetopon (Schmidhammer et al, 1990) were prepared according to the previously described procedures. Morphine (10 mg/ml) was purchased from Pharmacia and Upjohn (Stockholm, Sweden).…”

“…In addition, antinociceptive effects on inflammatory pain after s.c. administration of 14-methoxymetopon ( Fig. 1) (Schmidhammer et al, 1990;Fü rst et al, 1993;Zernig et al, 2000;King et al, 2003), a centrally acting -opioid receptor agonist, are described.…”

Mu Opioids and Their Receptors: Evolution of a Concept

“…1B). One particularly interesting derivative is 14-hydroxymetopon (Schmidhammer et al, 1990;Fürst et al, 1993;Freye et al, 2000;King et al, 2003). This derivative is an exceedingly potent analgesic with limited respiratory depression or inhibition of gastrointestinal transit.…”

Peripheral versus Central Antinociceptive Actions of 6-Amino Acid-Substituted Derivatives of 14-O-Methyloxymorphone in Acute and Inflammatory Pain in the Rat

“…1). Further chemical optimization led to 14-methoxymetopon (Schmidhammer et al, 1990; Fig. 1), a highly selective -opioid receptor agonist (Fü rst et al, 1993;Spetea et al, 2003).…”