Effect of substitution of glycine by D- or L-alanine on the activity of the C-terminal hexapeptide analogue of substance P on isolated guinea-pig ileum.
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Amino Acid Sequence↗
Biomedical subjects
A W Lipkowski
Publications and source records attributed to A W Lipkowski.
Contracting activity of C-terminal fragments and a C-terminal hexapeptide analogue of substance P on non-stimulated and electrically stimulated isolated guinea-pig ileum.
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Animals↗
Local increases of subcutaneous beta-endorphin immunoactivity at the site of thermal injury.
To examine interactions between exogenous opioid analgesia and endogenous opioid generation at a site of burn-induced tissue injury, we measured beta-endorphin (BE) and corticosterone (C) in aliquots of plasma and wound fluid withdrawn from subcutaneous wire mesh chambers beneath the site of a 3-5% surface area burn. After brief inhalational anesthesia at the time of thermal injury, rats received morphine (4 mg/kg, single dose), fentanyl (0.02 mg/kg hourly for 4 h), or no opioid. Systemic hormone responses and behavioral changes were minimal as expected for the minimal percentage burn. In all three groups intrachamber BE and C rose above baseline at 1, 2 and 4 h postburn, then returned to baseline at 24 h. Systemic opioid treatment produced analgesia (by tail flick latency testing) but did not reduce intrachamber hormone responses. Thus local BE and C responses at the site of thermal injury are regulated differently from systemic pituitary-adrenal responses.
Analgesics, Opioid↗
Double-enkephalins--synthesis, activity on guinea-pig ileum, and analgesic effect.
We have synthesized enkephalin analogues in which C-terminal methionine or leucine residues are replaced by a second active fragment of the enkephalin analogue. Synthesis of two compounds is described: in one, two fragments of a D-Ala2-enkephalin analogue are connected by a -NH-NH-bridge, and in the other, three methylene groups are incorporated between the amino groups. The first compound is a very potent inhibitor of electrically induced contractions of guinea-pig ileum and produces a strong analgesia when administered intraperitoneally in mice. The second compound is less active on the ileum and fails to produce analgesia after systemic injection. The double-enkephalins may interact with mu-receptors.
Analgesia↗
The effect of enkephalin dimers on body temperature in mice.
Short-lasting decrease in rectal temperature in mice after intraperitoneal administration of an enkephalin dimer, the so called double-enkephalin--(Tyr-D-Ala-Gly-Phe-NH)2 (D-ENK-O)--at dose 0.1, 0.5, 1, 2.5, 5, 10 and 20 mg/kg of body weight was observed. Another double-enkephalin--Tyr-D-Ala-Gly-Phe-NH-(CH2)3-HN-Phe-Gly-D-Ala-Tyr-- fai led to produce this effect. The hypothermic effect of D-ENK-O was almost completely reduced by naloxone which suggests an involvement of opiate receptors in the D-ENK-O produced hypothermia in mice.
Animals↗
Comments on Smith and Smith (PAIN, 62 (1995) 51-60)
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Analgesics, Opioid↗
A topographical model of mu-opioid and brain somatostatin receptor selective ligands. NMR and molecular dynamics studies.
We have refined the 1H NMR-based conformations of the mu-opioid receptor selective peptides related to somatostatin of general formula Xxx-Yyy1-Cys-Zzz-D-Trp-Lys(Orn)5-Thr-Pen-Thr8- NH2, where Xxx, Yyy, Zzz are 0, D-Phe and Tyr for 1; 0, D-Tic and Tyr for 2; Gly, D-Tic and Tyr for 3; and 0, D-Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275-2283), using a molecular-dynamics approach. We present evidence that the NMR data are compatible with beta II'-, gamma- and gamma'-turns for the central tetrapeptide Tyr-D-Trp-Lys/Orn-Thr. Based on detailed structural and topographical considerations, we suggest that the mu-opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of D-Tic1 and Tyr3 (7.5 A), and that the opioid receptor recognition domain is located in the N-terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a mu-opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.
Amino Acid Sequence↗
Bifunctional pharmacophores. Biological activities of the peptide analog containing both casomorphine-like and substance P antagonist-like active elements.
SP-antagonistic properties of a newly synthesized peptide Tyr-Pro-D-Phe-Phe-D-Phe-D-Trp-MetNH2 (AWL-60) were investigated both in vitro and in vivo. In vitro AWL-60 effectively antagonized the action of SP-agonist (SP6-11); however, this antagonism was non-competitive. Antagonistic properties of AWL-60 were also observed in vivo: in doses as low as 0.1 nmol/kg iv AWL-60 markedly attenuated the fall in blood pressure produced by [less than Glu]6SP6-11. Since AWL-60 exerts weak opioid agonistic properties (as a casomorphine analog) the possible involvement of an opioid agonistic component in their SP inhibitory action is considered.
Amino Acid Sequence↗
Cooperative reinforcement of opioid pharmacophores.
In recent years several opioid receptors have been characterized (mu, kappa, delta, et cetera); furthermore, it has been suggested that different receptor types mediate different neurophysiological responses. It has also been found that there exist endogenous opioid peptides which reveal some selectivity for a particular receptor type. These observations created a need for selective agonists and antagonists of a particular receptor type, and indicated a possibility of developing selective opioid drugs with reduced side effects. All endogenous peptides have an identical N-terminal part, which suggests that opioid receptor pockets in the message part are similar or identical. The main elements which differentiate the selectivity of endogenous peptides are surroundings of receptor pockets, different organization of opioid receptors and their interactions with other receptors and enzymatic systems. This opens a possibility of successful modifications of biochemical and/or physiological properties of opioid pharmacophores through modification of the elements which could be connected with the opioid message. Depending on the character of the connecting element, the pharmacophores may be divided into three main types: (i) opioid pharmacophores coordinated with the address; (ii) bivalent opioids; (iii) bifunctional pharmacophores.
Animals↗
Non-deterministic individual responses to receptor-selective opioid agonists.
To assess within a single rat strain individual variability of analgesic responses to sub-ED50 doses of receptor-selective opioids, we measured: 1) tail flick latency (TFL) responses after intrathecal (ith) injection of delta, mu, and kappa agonists administered serially; 2) TFL and tail pinch latencies (TPch) after intravenous (iv) mu and kappa agonists; and 3) TFL and TPch after iv agonists of mu or combined mu + delta selectivity. Mean values in each study confirmed an analgesic response, but individual TFL and TPch responses were chaotic and, within each study, rank order correlations between TFL and TPch values within or between drugs were insignificant. Our results suggest a hypothesis that such responses are intrinsically nondeterministic because--resembling other complex dynamic systems--they are generated by stochastic receptor-transmitter interactions that in turn evoke a series of nonlinearly coupled cellular and neural events.
Amino Acid Sequence↗