Synthesis and antinociceptive activity of peptides related to interleukin-1 beta 193-195 Lys-Pro-Thr.
To obtain information about the structure-activity relationships of analgesic peptides, we modified the previously reported tripeptide, H-Lys-Pro-Thr-OH (C). The proline part in C was replaced with various analogues of unconventional amino acids [(3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic), (S,S,S,)-2-azabiciclo [3.3.0]octane-3-carboxylic acid (Aoc), D-Aoc, and (2S, 4R)-hydroxyproline (Hyp)] with varying lipophilic, steric, and conformational properties, and alternatively with Lys and Orn in the lysine part. Moreover, the threonine part was changed to various natural amino acids (Ser, Thr, Val, Leu). All the compound were screened in vivo for their analgesic effects in mouse writhing test. Compound 24 (H-Orn-Hyp-Val-OH), the most active compound within the series, showed an ED50 value of 10 mg/kg, which is comparable with the ED50 values exhibited by indometacin (4.1 mg/kg) and the dipeptide H-Lys-D-Pro-OH (6.9 mg/kg), both used as reference drugs.
Caliendo
G
G
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Italy.
Greco
G
G
Grieco
P
P
Perissutti
E
E
Santagada
V
V
Ialenti
A
A
Maffia
P
P
Albrizio
S
S
Santini
A
A
D019342:Acetic Acid; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D007375:Interleukin-1 / Q000737:chemistry / Q000494:pharmacology*; D053583:Interleukin-1beta; D008297:Male; D051379:Mice; D010147:Pain Measurement; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000700:Analgesics; D007375:Interleukin-1; D053583:Interleukin-1beta; D010446:Peptide Fragments; C056932:interleukin 1beta (193-195); D019342:Acetic Acid