Syntheses, opioid binding affinities, and potencies of dynorphin A analogues substituted in positions, 1, 6, 7, 8 and 10.
Structural, stereochemical, stereoelectronic and conformational requirements for biological activity of dynorphin A1-11-NH2 analogues at opioid receptors were explored by substitution of Tyr1, Arg6, Arg7, Ile8 and Pro10 with other amino acid residues. Interestingly, substitution of Tyr1 with N alpha-Ac-Tyr1, D-Tyr1, Phe1 or p-BrPhe1 led to analogues that were quite potent at kappa opioid receptors, and additional substitution of Ile8 with D-Ala8 and/or Pro10 with D-Pro10 retained high potency in brain binding assay: [N alpha-Ac-Tyr1]- (1), [D-Tyr1]-(2) [Phe1]- (3), [Phe1,D-Ala8]- (5), [-BrPhe1, D-Ala8]- (6), [Phe1, D-Pro10]- (7) and [Phe1,D-Ala8, D-Pro10]- Dyn A1-11-NH2 (8) had IC50 (nM) binding affinities of 13.2, 18.6, 1.64, 1.26, 1.84, 2.44 and 1.62 nM, respectively. The D-Phe1 analogue 4, however, was only weakly active (610 nM). All of the analogues except 4 were modestly selective for kappa vs. mu guinea pig brain opioid receptor (11- to 88-fold) and quite selective for kappa vs. delta receptors (65-576). However, all of the analogues appeared to have very low or essentially no activity in the guinea pig ileum and mouse vas deference functional bioassays, and one analogue, 5, appeared to have weak antagonist activities. On the other hand, if constrained amino acids such as beta-methylphenylalanine or 1,2,3,4-tetrahydroisoquinoline carboxylic acid, and hydroxyproline were placed in the 1 position, inactive analogues or analogues with greatly reduced potency and biological activity were obtained (compounds 12-14). It had previously been suggested that the Arg6 and Arg7 residues were critical for biological activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Kawasaki
A M
AM
Department of Chemistry, University of Arizona, Tucson.
Knapp
R J
RJ
Walton
A
A
Wire
W S
WS
Zalewska
T
T
Yamamura
H I
HI
Porreca
F
F
Burks
T F
TF
Hruby
V J
VJ
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D004723:Endorphins / Q000378:metabolism*; D006168:Guinea Pigs; D051379:Mice; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004723:Endorphins; D011957:Receptors, Opioid; D004399:Dynorphins