Opiate antagonists stimulate the release of LH and might, therefore, contribute to an innovative therapy for the treatment of numerous clinical syndromes characterized by hypofnnction 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, groups were introduced at the crucial 14D-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 1la-C were stronger antagonists than naltrexone, whereas Pr and PhCH, substituents in l l c , l l d , 9d, 9d3, 9d4, and 9d5 led to orally active LH stimulators. Based on our finding that the y-antagonists 12 and lib5 showed no LH stimulation, we conclude that a Combination of both p -and x-antagonism is necessary for potent LH stimulation.
Introduction. -Endogenous opiate peptides (EOP's) of the CNS participate in the regulation of the hypothalamo-hypophyseal-gonadal (HHG) axis. In rodents as well as in primates, the administration of opiate agonists leads to suppression of the secretion of luteinizing hormone (LH), while on the other hand, increased release of LH follows the application of opiate antagonists [ 11. Hypofunction of the HHG axis underlies numerous clinical syndromes such as the hypothalamic syndrome, idiopathic hypogonadotrophic hypogonadism, secondary hypothalamic hypogonadism, Kullmun's syndrome, delayed puberty, adolescent menstrual disorders, anorexia nervosa, and stress-related disorders. The presently available therapeutic approaches -human gonadotrophin, anti-estrogens, and pulsatile LHRH -all have inherent drawbacks and limitations associated with them. Opiate antagonists as LH secretion stimulators, therefore, represent a potential novel approach to their treatment.
With the above background in mind, we have attempted to synthesize potent, longacting, and orally active opiate antagonists as LH-secretion stimulators. In the present article, we describe the design, synthesis, and LH-stimulating activities of a series of novel 14P-alkylated N-(cyclopropylmethy1)morphinans and -4,5a -epoxymorphinans.
Design of Pure Opiate Antagonists. -Opiate antagonists with partial agonistic activity are of no interest as potential therapeutic agents for endocrine disorders, as they bear the danger of producing opioid side effects such as addiction or respiratory depression. We, therefore, deemed it necessary to design and develop pure opiate antagonists. The successful design of pure opiate antagonists is facilitated by the structure-activity relationships established over the past two decades. Replacement of an opiate N-methyl group in 14P-unsubstituted morphinans, 4,5a -epoxymorphinans, or 9P-unsubstituted ') Minimum-energy conformations for equatorial and axial N-conformers (protonated) were calculated using SEARCH and MAXIMIN functions.