Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-10-02
1994-05-31
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31114
Patent
active
053170229
DESCRIPTION:
BRIEF SUMMARY
The subject of the invention is a biologically active composition for selective blocking of the opiate binding sites of the bran which are responsible for respiratory depression, which contains codeinone derivatives of the general formula (I) or its salts in a biologically active quantity.
In this specification the substituents of changing signification are always the following: such which can be transformed into said groups. respiratory-depressants. On the course of acute toxicity investigations lethality of such compounds is attributed to this activity [Prog. Neurobiol. 33(1984)1-16; 22(1984) 345].
Interpretation of relations between respiratory depressant activity and opiate receptors is rather difficult. According to the present conceptions there are several receptors which might participate in mediating this effect. However the relative contribution of various receptor populations mediating this effect is not clear enough. Since evaluating the respiratory parameters is complicated, selectivity of the methods is questionable and because of the big differences amongst the species the difficulties are further increased. The difficulties and problems inherent in these methods partially explain the difference in receptor assignments in opioid induced respiratory depression which have appeared in literature.
Several biochemical and pharmacological data prove the heterogeneity of the opioid receptors both in the neurological system and in the periferies [Trends. Neuro. Sci. 7.(1984) 31; Pharmac. Rev. 39 197-249 (1987).]
The main receptors--marked .mu., .delta., . and .sigma. receptors--show different dispersity in the different tissues, have different ligand specifities and mediate different physiological processes. In recent times it was clarified also that these main receptor types can be divided into sub-types. From these in the case of the .mu. type receptor it is possible to distinguish .mu..sub.1 and .mu..sub.2 sub types. It is suggested that the .mu..sub.1 receptor mediates the analgesic effects of opiates while the .mu..sub.2 mediates opioid induced respiratory depression.
Identification of these two sub types of opioid receptors may be brought about by way of their binding capacity to opioid receptors of so called high and low affinity. Ligands for .mu..sub.1 receptors are bound to the high affinity (.sup.3 H)naloxone binding sites. (Their affinity constants are below nanomole concentrations.) The .mu..sub.2 receptors (low affinity binding sites) mediates among others, opioid induced respiratory depression. (Their affinity constants are in the range of nanomole concentration or above.)
Ligands are known which are capable to inhibit selectively the .mu..sub.1 receptors. E.g. naloxonazine, oximorphazone, several other C-6 morphinane derivatives and interestingly also some peptides (the chloro-methyl ketones of encephalines) are of this group.
As far as we are aware no compounds capable to block the .mu..sub.2 receptors were known hitherto. It is our observation that codeinone, oxycodone and dihydrocodeinone derivatives substituted in position C-6 are bound in a partially irreversible manner to .mu..sub.2 receptors.
It has to be mentioned however that the existence of .mu..sub.1 and .mu..sub.2 receptors has not yet found general acceptance. There were several who could not repeat the experiment which serves as main proof namely that the respiratory depression caused by morphine is not inhibited by the selective .mu..sub.1 antagonist naloxonazine.
A further difficulty may be caused also by analysis of the complex action of opiates on respiration. There are opiates known which are depressing (.mu.-agonists: morphine etc.), others which are stimulating (receptor agonists: cyclazocine) and others which have dualistic (deprimating and stimulating) effects (partial antagonists: nalorphine).
The significance of identification of the .mu..sub.2 receptor would be in theory and in practice that knowing the same there would be a possibility to synthesize such compounds which would not have respiratory depressing
REFERENCES:
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Receptor Binding and Analgesic Properties of Oxymorphazone, S. Galetta, et al., Life Sciences, (1983) vol. 31, pp.1389-1392.
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Synthesis and Binding of .sup.3 H-Oxymorphazone to Rat Brain Membranes, E. Varga, et al., Life Sciences, vol. 40, pp. 1579-1588 (1987).
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Opiate and Analgesia: Evidence for Mediation by a Subpopulation of Opiate Receptors, Science (1980) vol. 208, pp. 514-516.
Classification of Opioid Receptors, S. J. Paterson, et al., British Medical Bulletin (1983) vol. 39, No. 1 pp. 31-36.
Naloxazone, a Long-Acting Opiate Antagonist: Effects on Analgesia in Intact Animals and on Opiate Receptor Bkinding in Vitro, G. W. Pasternak, et al., Journal of Pharmacology and Exper. Therap. (1980) vol. 214, No. 3, pp. 455-462.
Benyhe Sandor
Borsodi Anna
Friedmann Tamas
Furst Zsuzsa
Hosztafi Sandor
Alkaloida Chemical Company Ltd.
Hook Gregory
Waddell Frederick E.
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