TY - JOUR
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
AU - Davis, Peg
AU - Yamamura, Henry I.
AU - Porreca, Frank
AU - Hruby, Victor J.
PY - 1996/3/1
Y1 - 1996/3/1
N2 - 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.
AB - 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.
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U2 - 10.1021/jm950369c
DO - 10.1021/jm950369c
M3 - Article
C2 - 8676350
AN - SCOPUS:0029933436
SN - 0022-2623
VL - 39
SP - 1136
EP - 1141
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -