Synthesis of an affinity ligand (‘UPHIT’) for in vivo acylation of the κ‐opioid receptor

FEBS Letters

Rice, Kenner C.¹  Band, Linda³  de Costa, Brian R.¹  Pert, Agu²  Rothman, Richard B.³  Bykov, Victor³  Jacobson, Arthur E.¹ 

[1] Laboratory of Medicinal Chemistry, National Institute of Digestive, Diabetes, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA;Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892, USA

关键词: Opioid agonist;    κ-;    Opioid receptor agonist;    U50;    488;    Site-directed affinity ligand;    Receptor;    κ-;    Intracerebroventricular administration;    Isothiocyanate analog;   

DOI  :  10.1016/0014-5793(89)80619-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The isothiocyanate analog (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, 3a) of the highly selective κ-opioid receptor agonist, U50,488, was prepared as a potential site-directed affinity ligand for acylation of κ-opioid receptors in vivo. The isothiocyanate (3a) which we have designated UPHIT and its enantiomer (3b) were synthesized in 3 steps starting from optically pure (1S,2S)-(+)-trans-2-pyrrolidinyl-N-methyl-cyclohexylamine (4a) and its enantiomer (4b), respectively, thus defining their absolute stereochemistry. Binding in vitro of the 1S,2S enantiomer 3a to κ receptors labelled by [³H]U69,593 was shown to occur with an IC₅₀ value of 25.92 ± 0.36 nM, whereas 827.42 ± 5.88 and 115.10 ± 1.23 nM were obtained for the IC₅₀ value of the 1R,2R enantiomer (3b) and (±)-3 respectively. Intracerebroventricular (ICV) injection of 100 μg of (±)-3 into guinea-pig brain followed by analysis of remaining κ-binding sites 24 h later revealed that (±)-3 depleted 98% of the κ receptors that bind [³H]U69,593 and 40% of those that bind [³H]bremazocine. These preliminary data suggest exciting uses for these compounds in furthering our knowledge of the κ-opioid receptor.

【 授权许可】

Unknown