Abstract
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.
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 57-62 |
| Seitenumfang | 6 |
| Fachzeitschrift | |
| Jahrgang | 6 |
| Ausgabenummer | 1 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - Jan. 1998 |
ÖFOS 2012
- 301207 Pharmazeutische Chemie
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Guerrini, R., Capasso, A., Marastoni, M., Bryant, S. D., Cooper, P. S., Lazarus, L. H., Temussi, P. A., & Salvadori, S. (1998). Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors. , 6(1), 57-62. https://doi.org/10.1016/s0968-0896(97)10008-6
Guerrini, R ; Capasso, A ; Marastoni, M et al. / Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors. in: . 1998 ; Band 6, Nr. 1. S. 57-62.
@article{13f01984f02b4ad4b2b0062af47279ac,
title = "Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors",
abstract = "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.",
keywords = "Analgesics, Opioid/chemical synthesis, Animals, Dose-Response Relationship, Drug, Drug Design, Dynorphins/chemical synthesis, Electrophysiology, Guinea Pigs, Ileum, Isoquinolines/chemistry, Muscle Contraction/drug effects, Muscle, Smooth/drug effects, Oligopeptides/chemistry, Peptide Fragments/chemical synthesis, Rabbits, Receptors, Opioid, delta/antagonists & inhibitors, Receptors, Opioid, kappa/antagonists & inhibitors, Receptors, Opioid, mu/antagonists & inhibitors, Structure-Activity Relationship, Tetrahydroisoquinolines",
author = "R Guerrini and A Capasso and M Marastoni and Bryant, {S D} and Cooper, {P S} and Lazarus, {L H} and Temussi, {P A} and S Salvadori",
year = "1998",
month = jan,
doi = "10.1016/s0968-0896(97)10008-6",
language = "English",
volume = "6",
pages = "57--62",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",
publisher = "PERGAMON-ELSEVIER SCIENCE LTD",
number = "1",
}
Guerrini, R, Capasso, A, Marastoni, M, Bryant, SD, Cooper, PS, Lazarus, LH, Temussi, PA & Salvadori, S 1998, 'Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors', , Jg. 6, Nr. 1, S. 57-62. https://doi.org/10.1016/s0968-0896(97)10008-6
Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors. / Guerrini, R; Capasso, A; Marastoni, M et al.
in: , Band 6, Nr. 1, 01.1998, S. 57-62.
Veröffentlichungen: Beitrag in Fachzeitschrift › Artikel › Peer Reviewed
TY - JOUR
T1 - Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors
AU - Guerrini, R
AU - Capasso, A
AU - Marastoni, M
AU - Bryant, S D
AU - Cooper, P S
AU - Lazarus, L H
AU - Temussi, P A
AU - Salvadori, S
PY - 1998/1
Y1 - 1998/1
N2 - 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.
AB - 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.
KW - Analgesics, Opioid/chemical synthesis
KW - Animals
KW - Dose-Response Relationship, Drug
KW - Drug Design
KW - Dynorphins/chemical synthesis
KW - Electrophysiology
KW - Guinea Pigs
KW - Ileum
KW - Isoquinolines/chemistry
KW - Muscle Contraction/drug effects
KW - Muscle, Smooth/drug effects
KW - Oligopeptides/chemistry
KW - Peptide Fragments/chemical synthesis
KW - Rabbits
KW - Receptors, Opioid, delta/antagonists & inhibitors
KW - Receptors, Opioid, kappa/antagonists & inhibitors
KW - Receptors, Opioid, mu/antagonists & inhibitors
KW - Structure-Activity Relationship
KW - Tetrahydroisoquinolines
U2 - 10.1016/s0968-0896(97)10008-6
DO - 10.1016/s0968-0896(97)10008-6
M3 - Article
C2 - 9502105
VL - 6
SP - 57
EP - 62
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 1
ER -
Guerrini R, Capasso A, Marastoni M, Bryant SD, Cooper PS, Lazarus LH et al. Rational design of dynorphin A analogues with delta-receptor selectivity and antagonism for delta- and kappa-receptors. . 1998 Jan;6(1):57-62. doi: 10.1016/s0968-0896(97)10008-6
