Syntheses of novel pyridazinomorphinans by inverse electron demand cycloaddition and their binding to mu and kappa receptors.
A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a and 16 have been evaluated for their affinity at mu and kappa opioid receptors in radioligand binding assays. Their ability to inhibit [3H]DAMGO binding at mu and [3H]U 69.593 binding at kappa receptors, respectively as compared to codeine has been found to be lower.
Klindert
T
T
Pharmazeutisch-Chemisches Institut der Universität Marburg, Marburg/Lahn, Germany.
Stroetmann
I
I
Seitz
G
G
Höfner
G
G
Wanner
K T
KT
Frenzen
G
G
Eckhoff
B
B
D000818:Animals; D044482:Benzeneacetamides; D001667:Binding, Competitive; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D007202:Indicators and Reagents; D008958:Models, Molecular; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*
D044482:Benzeneacetamides; D004745:Enkephalins; D007202:Indicators and Reagents; D009019:Morphinans; D011719:Pyrazines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C045444:U 69593