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Design and Synthesis of Novel Opiate Antagonists with LH‐Stimulating Properties
Author(s) -
Revesz Laszlo,
Siegel Richard A.,
Buescher HansHeinz,
Marko Magda,
Maurer Richard,
Meigel Harald
Publication year - 1990
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19900730212
Subject(s) - chemistry , opiate , naltrexone , antagonism , pharmacology , stimulation , thebaine , stereochemistry , antagonist , endocrinology , morphine , receptor , biochemistry , medicine , codeine
Opiate antagonists stimulate the release of LH and might, therefore, contribute to an innovative therapy for the treatment of numerous clinical syndromes characterized by hypofunction of the HHG axis. The purpose of this work was to design and synthesize pure opiate antagonists useful for this therapy. Me, Et, Pr, and PhCH 2 groups were introduced at the crucial 14β‐position of morphines and morphinans via a hetero‐ Diels ‐ Alder key step starting from thebaine derivative 1 and tested for opiate antagonism and LH‐stimulating activity. Me‐, Et‐, and Pr‐substituted compounds 11a – c were stronger antagonists than naltrexone, whereas Pr and PhCH 2 substituents in 11c , 11d , 9d , 9d 3 , 9d 4 , and 9d 5 led to orally active LH stimulators. Based on our finding that the μ‐antagonists 12 and 11b 5 showed no LH stimulation, we conclude that a combination of both μ‐and χ‐antagonism is necessary for potent LH stimulation.