Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH21

Feng Di T Lung, Nathan Collins, Dagmar Stropova, Peg Davis, Henry I. Yamamura, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

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Abstract

We previously have reported four possible binding conformations of dynorphin A (Dyn A) for the central κ opioid receptors, induced by the address sequence, using a molecular mechanics energy minimization approach. The lowest energy conformation was found to exhibit an α-helical conformation in the cyclized address sequence. It was suggested that an α-helical conformation in the cyclized address sequence or a helical conformation induced by the conformational characteristics of the message sequence may be important for binding potency and κ opioid receptor selectivity. Side chain to side chain lactam bridges between the i and i + 4 positions have been shown to stabilize α-helical conformations. Thus, a series of cyclic lactam analogues of dynorphin A(1-11)-NH2 have been designed, synthesized and evaluated by the guinea pig brain (GPB) binding assay and guinea pig ileum (GPI) bioassay to evaluate the conformational analysis prediction and, further, to investigate the conformational requirements for high potency and selectivity for κ opioid receptors. Positions 2-6, 3-7, and 5-9 were chosen as the sites for incorporating cyclic conformational constraints. Cyclization between D-Asp2 and Lys6 in c[D-Asp2,Lys6]Dyn A(1-11)-NH2 led to an analogue with pronounced potency and selectivity enhancement for the μ opioid receptor, whereas cyclization between D-Asp3 and Lys7 in c[D-Asp3,Lys7]Dyn A(1-11)-NH2 led to a potent ligand (IC50 4.9 nM) with κ receptor selectivity. The other analogues in the series proved to be less selective. The biological results led to the suggestion that the binding conformation for the κ receptor may have structural requirements that are distinct from those of μ and δ receptors. Interestingly, analogues with a D-Asp at position 2, 3, or 9 were found to be more potent for the κ receptor than analogues with an L-Asp at the same positions. It is suggested that the incorporation of D-Asp into position 2, 3, or 9 of Dyn A(1-11)-NH2 may have stereochemical and conformational effects on the nearby amino acids which can help discriminate the preference between κ, μ, and δ receptors.

Original languageEnglish (US)
Pages (from-to)1136-1141
Number of pages6
JournalJournal of Medicinal Chemistry
Volume39
Issue number5
StatePublished - Mar 1 1996

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Dynorphins
Lactams
Cyclic Peptides
Opioid Receptors
Bioactivity
Conformations
Peptides
Cyclization
Guinea Pigs
Mechanics
Ileum
Biological Assay
Inhibitory Concentration 50
Molecular mechanics
Ligands
Bioassay
Amino Acids
dynorphin A (1-11)-amide
Brain
Assays

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH21. / Lung, Feng Di T; Collins, Nathan; Stropova, Dagmar; Davis, Peg; Yamamura, Henry I.; Porreca, Frank; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 39, No. 5, 01.03.1996, p. 1136-1141.

Research output: Contribution to journalArticle

Lung, Feng Di T ; Collins, Nathan ; Stropova, Dagmar ; Davis, Peg ; Yamamura, Henry I. ; Porreca, Frank ; Hruby, Victor J. / Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH21. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 5. pp. 1136-1141.
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T1 - Design, synthesis, and biological activities of cyclic lactam peptide analogues of dynorphin A(1-11)-NH21

AU - Lung, Feng Di T

AU - Collins, Nathan

AU - Stropova, Dagmar

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AU - Yamamura, Henry I.

AU - Porreca, Frank

AU - Hruby, Victor J

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