Role of associative and nonassociative mechanisms in tolerance to morphine "anorexia".

To determine whether tolerance to morphine-induced anorexia involves associative mechanisms, rats were given chronic injections of morphine (Group 1, 10 mg/kg; Group 2, 20 mg/kg) in the presence of one compound cue on alternate days and injections of saline in the presence of another compound cue on the intervening days. After tolerance developed to the initial suppression of intake, three tests of Pavlovian conditioning were conducted. On the compensatory response test, in which saline injections were given in the presence of the morphine cue, only Group 2 showed a significant increase in milk intake. On the explicit unpairing test and the environmental specificity test, in which morphine injections were given in the presence of the saline cue or in an entirely different room, respectively, neither group showed a significant loss of tolerance. The failure to demonstrate cue-dependent tolerance in this paradigm may have been due in part to inadvertent temporal conditioning and in part to the rapid development of nonassociative tolerance.

Tolerance to morphine "anorexia" is not contingent on experience with food while in the drugged state.

To determine whether tolerance to morphine-induced anorexia requires access to milk while intoxicated, rats were given chronic injections of morphine (10 or 20 mg/kg) either before (before subgroups) or after (after subgroups) access to milk on alternate days. There were marked individual differences in initial sensitivity to the drug. After chronic treatment, there was little difference in the level of tolerance in subjects given morphine either before or after access to milk. On the intervening nondrug days, rats in the before subgroups consistently drank less milk than the other subgroups. This effect was not the result of withdrawal distress. Substitution of saline for morphine (20 mg/kg) on a scheduled drug day resulted in enhanced milk intakes in both the before and after subgroups. The results suggest that tolerance to morphine anorexia does not involve instrumental learning.

Enzyme inactivation by potential metabolites of an aromatase-activated inhibitor (MDL 18,962).

MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metabolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17 beta-hydroxy steroid oxidoreductase, 6 beta-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P450 steroid 6 beta-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent Ki and t1/2 at infinite inhibitor concentration (tau 50) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13 nM, 37 min for 6 beta-hydroxy analog; and 167 nM, 6.1 min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6 beta-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.

Pharmacological induction of 5 alpha-reductase deficiency in the rat: separation of testosterone-mediated and 5 alpha-dihydrotestosterone-mediated effects.

(5 alpha, 20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5 alpha-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles,and preputial glands, but had no effect on growth of the levator ani muscle. (5 alpha-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5 alpha-dihydrotestosterone (5 alpha-DHT). The inhibitor thus produced a pure 5 alpha-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5 alpha-reductase-deficient human male: reduction of 5 alpha-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5 alpha-DHT. Evidence is presented which indicates that the testes are the source of circulating 5 alpha-DHT in the immature rat.

Endocrine properties of RMI 12,936, an antiprogestational steroid.

RMI 12,936 (17 beta-hydroxy-7 alpha-methyl-5-androstene-3-one) exhibited postcoital contragestative activity at 10 mg/kg in hamsters. The endocrinological profile was determined for this steroid. This antifertility agent had significant antiprogestational, antiuterotrophic and gonadotropin-inhibiting activity. RMI 12,936 also exhibited weak uterotrophic and androgenic properties when given to immature gonadectomized rats. Hormonal antagonism and weak estrogen agonist properties would appear to contribute to the contragestative activity of RMI 12,936 in hamsters.

Stereochemistries of geometric isomers of 4-(2-bromo-1,2-diphenylvinyl)phenol, 4-(2-bromo-1,2-diphenyylamine: corrections of the literature.

The stereochemistries of geometric isomers of 4-(2-bromo-1,2-diphenylvinyl)phenol, 4-(2-bromo-1,2-diphenylvinyl)anisole, and 2-[p-(2-bromo-1,2-diphenylvinyl)phenoxy]triethylamine were determined by conversion of the phenolic analog to the ethers and subsequent comparison of physical properties with those of 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]triethylamine of known stereochemistry.

Antiprogestational agents. The synthesis of 7-alkyl steroidal ketones with anti-implantational and antidecidual activity.

A series of 7alpha- and 7beta- alkyl derivatives of steroidal 4-en- and 5-en-3-ones were prepared by 1,6-conjugate addition of organocopper reagents to various steroidal 4,6-dien-3-ones of the androstane, estrane and gonane series. Biological study of these and related compounds revealed that 17beta-hydroxy-7alpha-methyl-5-androsten-3-one (2), 17beta-hydroxy-7alpha-methyl-5-estren-3-one acetate and 17beta-hydroxy-7alpha-methyl-4-estren-3-one acetate had significant anti-implantational and antidecidual activities. The contragestative effects were associated with the latter anti-hormonal properties, and not with the androgenicity of these compounds.