D-Ala2,F5Phe4-dynorphin amide, an opiate with analgesic and toxic properties.
A novel analog of dynorphin (1-13), D-Ala2,F5Phe4-dynorphin amide, was prepared and its pharmacological spectrum of activity was investigated. In a hot plate test on Swiss Webster and C57Bl mice, a 20 micrograms intracerebroventricular (icv) dose of the analog produced analgesia, which was greater in potency and duration than the parent dynorphin. This action of D-Ala2,F5Phe4-dynorphin amide was antagonized by the opiate receptor antagonist naloxone (2 mg/kg ip), administered either before or after the peptide. In addition to its analgesic action in mice, D-Ala2,F5Phe4-dynorphin amide produced a Straub tail and a catatonic-like state, both of which were also attenuated by naloxone. On the electrically-stimulated mouse vas deferens preparation, in vitro, D-Ala2,F5Phe4-dynorphin amide inhibited contractile activity and had an IC50 of 108.2 +/- 34.7 nM (SEM), about 4-fold weaker than that of dynorphin. This action was also attenuated by naloxone. An icv dose of 150 micrograms of D-Ala2,F5Phe4-dynorphin amide in mice, and a cumulative series of icv doses up to 2600 micrograms in anesthetized rats, failed to produce a lethal effect. No pathological changes were observed in mouse liver and kidney at 24 h after a 50 mg/kg dose of the peptide analog. In rats anesthetized with diallylbarbital (70 mg/kg ip) and urethane (280 mg/kg ip), D-Ala2,F5Phe4-dynorphin amide did not modify blood pressure, heart rate and respiratory rate. However, when mice were injected peripherally with single doses of D-Ala2,F5Phe4-dynorphin amide, convulsive episodes were produced, and lethal effects were observed with an LD50 of 60.0 mg/kg (95% confidence limits: 49.7-70.2 mg/kg) at 48 h. This action of D-Ala2,F5Phe4-dynorphin amide was not attenuated by naloxone (2.0 mg/kg, ip). Although analgesic and behavioral effects of D-Ala2,F5Phe4-dynorphin amide (e.g. Straub tail and catatonic-like state) are opiate-like, the lethal effect may be the consequence of actions of the peptide on non-opiate systems, Thus, the novel fluorinated dynorphin analog, D-Ala2,F5Phe4-dynorphin amide, may be a useful chemical tool for the study of opiate systems and their occasionally unanticipated biological or toxic actions.
Kostrzewa
R M
RM
Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614.
Brus
R
R
Coy
D H
DH
Criswell
H
H
Coogan
P S
PS
Kastin
A J
AJ
D000700:Analgesics / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D010446:Peptide Fragments; C054641:dynorphin amide (1-13), Ala(2)-(5-F-Phe)(4)-; D009270:Naloxone; C026843:dynorphin (1-13); D004399:Dynorphins