Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: compounds with moderate to low opioid-receptor affinity.

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Li F, Folk JE, Cheng K, Kurimura M, Deck JA, Deschamps JR, Rothman RB, Dersch CM, Jacobson AE, Rice KC

Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: compounds with moderate to low opioid-receptor affinity.

Bioorg Med Chem. 2011 Jul 15;19(14):4330-7. doi: 10.1016/j.bmc.2011.05.035. Epub 2011 May 24.

PubMed ID

21684752 [ View in PubMed

]

Abstract

N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for mu- and kappa-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at mu- and kappa-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for mu- and kappa-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate mu- and kappa-opioid antagonist activity in the [(35)S]GTP-gamma-S assay (K(e)=31 and 26 nM).

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Morphine	Mu-type opioid receptor	Ki (nM)	2.55	N/A	N/A	Details