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.
Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614.
R M
RM
Kostrzewa
R
R
Brus
D H
DH
Coy
H
H
Criswell
P S
PS
Coogan
A J
AJ
Kastin
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