Biological tests for opiate activity of newly-synthesized compounds--opioid peptides and cyclic beta-diketones.
A group of newly-synthesized (Leu5) enkephalinamides and their derivatives, with incorporated D-amino acids, as well as a group of cyclic beta-diketones from the group of 1, 3-indandiones, were partially pharmacologically characterized in experiments in vivo and in vitro. The substances studied, applied subcutaneously in doses of 50 to 1250 micrograms/kg bogy mass in mice, did not induce symptoms of acute and late toxicity. According to the parameters of the neuropharmacological screening tests performed, no significant differences were observed between the mice treated with the agents tested and the control mice. All five agents investigated significantly shortened the duration of hexobaribital-induced sleep. In the experiments using the conflict test after Vogel et al. (1971), (D-Ala2, D-Leu5) enkephalinamide induced a behavioural effect which can be qualified as anxiolytic. The same analogue also manifested a marked analgesic effect with the two tests used: hot plate test and the peritoneal test with glacial acetic acid. The cyclic beta-diketones-(methindiones) tested also manifested good analgesic effect with both test. (D-Ala2, D-Leu5), enkephalinamide strongly reduced the electrically induced contractile responses of the ileum. This effect was completely prevented by naloxone. The fact that (D-Ala2, D-Leu5) enkephalinamaide, known as a selective agonist of the delta-opiate receptors, proved to be particularly active suggests that both mu- and delta-type opiate receptors exist in the guinea-pig ileum. The pronounced analgesic effect of the leucine-enkephalinamide analogue with two substituted D-amino acids and of the two cyclic beta-diketone methindiones opens up new possibilities for synthesizing efficient analgesic agents.
Institute of Physiology, Bulgarian Academy of Sciences, Sofia.
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VD
Petkov
R
R
Radomirov
S
S
Minchev
D
D
Petkov
V
V
Alexiev
S
S
Stoev
K
K
Venkova
I
I
Mancheva
I
I
Stoyneva
V V
VV
Petkov
D000700:Analgesics; D000818:Animals; D004558:Electric Stimulation; D004743:Enkephalin, Leucine / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009294:Narcotics / Q000138:chemical synthesis / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects
D000700:Analgesics; D007189:Indans; D007192:Indenes; D009294:Narcotics; D010455:Peptides; C001723:methindione; D004743:Enkephalin, Leucine