Hans W. Kosterlitz

Bio: Hans W. Kosterlitz is an academic researcher from University of Aberdeen. The author has contributed to research in topics: Enkephalin & Opioid peptide. The author has an hindex of 44, co-authored 139 publications receiving 11075 citations. Previous affiliations of Hans W. Kosterlitz include Royal College of Surgeons of England.

Endogenous opioid peptides: multiple agonists and receptors

Abstract: Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties

Abstract: Four groups of narcotic analgesic drugs have been assessed for their opiate activities by using three binding assays and three pharmacological bioassays. In the binding assays, their inhibition constants (K I, nM) were determined against the binding of the μ-ligand, [3H]-[d-Ala 2 ,MePhe 4 , Gly-ol5]enkephalin, of the δ-ligand, [3H]-[d-Ala 2 ,d-Leu 5]enkephalin and of the ϰ-ligand, [3H]-(±)-ethylketazocine after suppression of μ- and δ-binding by 100 nM of the unlabelled μ-ligand and 100 nM of the unlabelled δ-ligand. The pharmacological agonist or antagonist activities were assayed on the guinea-pig ileum, mouse vas deferens and rat vas deferens. The first group of compounds were pure agonists in all three pharmacological bioassays. The majority of the compounds showed preference to μ-binding but phenazocine and particularly etorphine had also high affinities to the δ- and ϰ-binding sites. The second group consisted of N-allyl and N-cyclopropylmethyl homologues of the morphine, 3-hydroxymorphinan and normetazocine series which had agonist and antagonist activities in the guinea-pig ileum and mouse vas deferens but were pure antagonists in the rat vas deferens. In the binding assays, μ-binding and ϰ-binding were prominent. The third group was made up by the ketazocine-like compounds which in the guinea-pig ileum and mouse vas deferens were pure agonists and in the rat vas deferens pure antagonists. The binding spectrum showed particularly high binding to the ϰ-binding site. The fourth group was the antagonists which were devoid of agonist activity with the exception of diprenorphine and Mr 2266 which had retained some agonism. The binding spectrum showed considerable variation, naloxone in low concentration being a selective μ-antagonist, Mr 2266 having high affinities to the μ- and ϰ-binding sites and diprenorphine having considerable affinities to the μ-, δ- and ϰ-binding sites. Since each of the four groups of compounds, whether pure agonists, agonist-antagonists, ketazocine-like drugs or pure antagonists, shows independent varittions in the affinities to the μ- and ϰ-binding sites, their different pharmacological behaviour cannot be solely due to difference in the binding spectra.

Dynorphin 1-8 and dynorphin 1-9 are ligands for the κ-subtype of opiate receptor

Abstract: It is generally accepted that there are three subtypes of opiate receptor: µ, δ and κ. The main endogenous ligands for the µ-and δ-sites are Met5-enkephalin, Leu5-enkephalin and β-endorphin, whereas the putative endogenous ligands for the κ-binding site were unknown until recent observations suggested that dynorphin1–13 might be a candidate. The most convincing evidence for this view has been presented by Goldstein and his colleagues who showed that dynorphin1–13 is a specific endogenous ligand for the κ-receptor and has a high potency and long duration of action1–13. We show here that the sequences Leu5-enkephalyl-Arg-Arg-Ile (dynorphin1–8) and, particularly, Leu5-enkephalyl-Arg-Arg-Ile-Arg (dynorphin1–9) are selective ligands for the κ-binding site. Whereas dynorphin1–13 and dynorphin1–17 are relatively resistant to the action of peptidase and have a long duration of action in vitro after wash-out, dynorphin1–8 and dynorphin1–9 are readily degraded by peptidases and their duration of action is much shorter. For this and other reasons, the possibility will have to be considered that dynorphin1–8 or dynorphin1–9 may be transmitters or modulators at the κ-binding site while dynorphin1–13 and dynorphin1–17 may act hormonally, that is, at a distance from the site of release.

Effect of morphine on adrenergic transmission in the mouse vas deferens. assessment of agonist and antagonist potencies of narcotic analgesics

Abstract: 1. Morphine inhibits the electrically evoked (0.1-0.15 Hz, 1 ms) contractions of the longitudinal muscle of the mouse vas deferens but not of the rabbit, guinea-pig, rat, cat, hamster or gerbil. This effect is stereospecific and is antagonized by naloxone or naltrexone. 2. Normorphine is equiactive with morphine but its effects are more rapid in onset and decline. 3. In the mouse vas deferens, the resting outflow of tritium-labelled catecholamines is unaffected by morphine. The electrically evoked outflow is depressed by morphine or normorphine in a dose-dependent manner. The ID50 for inhibition of contraction and for depression of outflow is 0.5 muM. 4. The relative agonist potencies of compounds without antagonist component (codeine, pethidine, morphine, normorphine, heroin, levorphanol, Ba-20227, etorphine) show good correlation with the relative agonist potencies determined in the guinea-pig ileum and for analgesia in man. 5. For compounds with dual agonist and antagonist properties, the dose-response curves for agonist activity are shallow. When the lowest concentrations giving a depression of the contraction of the mouse vas deferens are used, a good correlation is obtained with the guinea-pig ileum. 6. The relative antagonist potencies of naloxone, nalorphine, levallorphan, and cyclazocine agree well with those obtained in the guinea-pig ileum; these, in turn, correlate well with the values obtained in the morphine-dependent monkey. 7. The fact that the agonist effects of drugs with dual agonist and antagonist action show little or no dependence on concentration, makes the mouse vas deferens particularly suitable for the assay of assay of antagonist activity. 8. As an assay preparation, the mouse vas deferens is less robust and consistent in its responses than the guinea-pig ileum.

Identification of two related pentapeptides from the brain with potent opiate agonist activity

Abstract: Enkephalin, a natural ligand for opiate receptors is composed of the pentapepides H-Tyr-Gly-Gly-Phe-Met-OH and H-Tyr-Gly-Gly-Phe-Leu-OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl-Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides.

Endogenous opioid peptides: multiple agonists and receptors

Abstract: Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.

Cellular and molecular mechanisms of drug dependence.

Abstract: The molecular and cellular actions of three classes of abused drugs--opiates, psychostimulants, and ethanol--are reviewed in the context of behavioral studies of drug dependence. The immediate effects of drugs are compared to those observed after long-term exposure. A neurobiological basis for drug dependence is proposed from the linkage between the cellular and behavioral effects of these drugs.

Turns in peptides and proteins.

Abstract: Publisher Summary Turns are a fundamental class of polypeptide structure and are defined as sites where the peptide chain reverses its overall direction. In the past 20 years, the peptide field has witnessed major development, stimulated by the discovery of a host of bioactive peptides. Turn structures have been proposed and implicated in the bioactivity of several of these naturally occurring peptides. In addition, many structural details of turns have been derived from conformational studies of model peptides. During this same period, more than 100 complete protein structures have been elucidated in single-crystal X-ray studies. These examples document the rich diversity of structural patterns in the chain folds of native proteins. Turns are intrinsically polar structures with backbone groups that pack together closely and side chains that project outward. Such an array of atoms may constitute a site for molecular recognition, and indeed, the literature abounds with suggestions that turns serve as loci for receptor binding, antibody recognition, and post-translational modification. In peptides, turns are the conformations of choice for simultaneously optimizing both backbone–chain compactness (intramolecular nonbonded contacts) and side-chain clustering (to facilitate intermolecular recognition). Presence of turns in bioactive conformations may in fact also reflect the lack of alternative conformational possibilities. The aim of this chapter is to examine structural and functional roles of turns in peptides and proteins.