Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.

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Spetea M, Windisch P, Guo Y, Bileviciute-Ljungar I, Schutz J, Asim MF, Berzetei-Gurske IP, Riba P, Kiraly K, Furst S, Al-Khrasani M, Schmidhammer H

Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.

J Med Chem. 2011 Feb 24;54(4):980-8. doi: 10.1021/jm101211p. Epub 2011 Jan 14.

PubMed ID

21235243 [ View in PubMed

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Abstract

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in delta and kappa activities, hence resulting in a loss of mu receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morphine	Kappa-type opioid receptor	EC 50 (nM)	484	N/A	N/A	Details
Morphine	Mu-type opioid receptor	EC 50 (nM)	316	N/A	N/A	Details