Guerrini R, Capasso A, Marastoni M, Bryant S D, Cooper P S, Lazarus L H, Temussi P A, Salvadori S
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Italy.
Bioorg Med Chem. 1998 Jan;6(1):57-62. doi: 10.1016/s0968-0896(97)10008-6.
Substitution of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in place of Gly2 in dynorphin A-(1-13)-NH2 and -(1-11)-NH2 (DYN) analogues (1 and 2) decreased the affinity to the kappa, delta, and mu receptors, and kappa selectivity. The analogue [D-Ala2, des-Gly3]DYN (4), a chimera between deltorphin/dermorphin N-terminal tripeptide and DYN, was virtually inactive for kappa-sites while the affinities for delta- and mu-receptors remained essentially unchanged. The doubly substituted analogue [2',6'-dimethyl-L-tyrosine (Dmt1)-Tic2]DYN (3) exhibited high delta-affinity (Ki=0.39 nM) while mu- and kappa-affinities were only an order of magnitude less (4-5 nM). Bioactivity of [Tic2]DYN peptides (1-3) on guinea-pig ileum and rabbit jejunum revealed potent delta- and kappa-antagonism, while the delta agonist potency of 4 was comparable to DYN. Thus, conversion from a kappa-agonist to antagonist occurred with the inclusion of Tic into DYN analogues, similar to the appearance of antagonist properties with delta- and mu-opioid agonists containing a Tic2 residue.
在强啡肽A-(1 - 13)-NH₂和-(1 - 11)-NH₂（DYN）类似物（1和2）中用1,2,3,4 - 四氢异喹啉 - 3 - 羧酸（Tic）取代甘氨酸₂会降低对κ、δ和μ受体的亲和力以及κ选择性。类似物[D - Ala₂，des - Gly₃]DYN（4）是强啡肽/皮啡肽N端三肽与DYN之间的嵌合体，对κ位点几乎无活性，而对δ和μ受体的亲和力基本保持不变。双重取代的类似物[2',6'-二甲基 - L - 酪氨酸（Dmt₁）- Tic₂]DYN（3）表现出高δ亲和力（Ki = 0.39 nM），而μ和κ亲和力仅低一个数量级（4 - 5 nM）。[Tic₂]DYN肽（1 - 3）对豚鼠回肠和兔空肠的生物活性显示出强效的δ和κ拮抗作用，而4的δ激动剂效力与DYN相当。因此，将Tic纳入DYN类似物会导致从κ激动剂转变为拮抗剂，这类似于含有Tic₂残基的δ和μ阿片样激动剂出现拮抗特性的情况。
