Abstract
Dicarba analogues of the cyclic opioid peptides H-Tyr-c[d-Cys-Gly-Phe-d(or l)-Cys]NH2 were synthesized on solid phase by substituting allylglycines for the cysteines and cyclization by ring-closing metathesis between the side chains of the allylglycine residues. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated -CH2-CH2- bridged peptides. The dicarba analogues retained high mu and delta agonist potencies. Remarkably, the trans isomer of H-Tyr-c[d-Allylgly-Gly-Phe-l-Allylgly]NH2 was a mu agonist/delta agonist with subnanomolar potency at both receptors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allyl Compounds / chemical synthesis
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Allyl Compounds / chemistry
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Allyl Compounds / pharmacology
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Animals
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Brain / metabolism
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Enkephalins / chemical synthesis*
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Enkephalins / chemistry
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Enkephalins / pharmacology
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Guinea Pigs
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Male
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Models, Molecular
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Molecular Conformation
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology
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Radioligand Assay
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Rats
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Receptors, Opioid, delta / agonists*
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Receptors, Opioid, mu / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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Allyl Compounds
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Enkephalins
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Peptides, Cyclic
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Receptors, Opioid, delta
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Receptors, Opioid, mu
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tyrosyl-cyclo(allylglycyl-phenylalanyl-allylglycyl)amide