pentolame and prolame

Alzheimer's disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aβ) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aβ

Topics: Amino Alcohols; Amyloid beta-Peptides; Estrenes; Estrogens; Models, Molecular; Protein Aggregates; Static Electricity

The 17β-aminoestrogens (AEs) prolame, butolame and pentolame are weakly oestrogenic in rodents and display anticoagulant properties in contrast to oestradiol (E

Topics: Amino Alcohols; Breast Neoplasms; Cell Proliferation; Estradiol; Estrenes; Estrogen Receptor alpha; Estrogen Receptor Antagonists; Estrogen Receptor beta; Estrogen Replacement Therapy; Female; Humans; MCF-7 Cells; Postmenopause; S Phase; Selective Estrogen Receptor Modulators

Estrogens of clinical use produce consistent antidepressant- and anxiolytic-like effects in animal models of menopause. Regulation of the hypothalamic-pituitary-adrenal (HPA) or stress axis, has been proposed as a pathway through which estrogens improve affective-like behaviors. Anticoagulant 17β-aminoestrogens (17β-AEs) butolame and pentolame mimic some effects of estradiol (E2), i.e., on female rodent sexual behavior, with opposite actions on coagulation. However, their psychoactive actions have not been explored. On the basis of similitude with E2's effects, we hypothesized that these 17β-AEs would induce anxiolytic- and antidepressant-like effects, which would be reflected in a reduction of activity in the HPA axis. In ovariectomized female rats, chronic treatment with prolame (60 μg/kg), butolame (65 μg/kg) and pentolame (70 μg/kg) reduced anxiety-like behavior in the elevated plus maze (evidenced by an increase in time in open arms, E2 (40 μg/kg) +176%; prolame +201%; butolame, +237%; and pentolame +295%, in comparison to the control vehicle group 100%). Pentolame also decreased significantly anxiety-like behavior in the burying behavior test. Prolame and E2 produced a significantly antidepressant-like action, which was not induced by butolame and pentolame. Behavioral effects of 17β-AEs (and E2) on anxiety and depression did not follow the same pattern than corticosterone or E2 levels; they also were associated to changes in locomotor activity, evaluated by the open field test. These results constitute the first evidence of specific and selective actions of butolame and pentolame as anxiolytics for females with a hypoestrogenic condition. Results also confirm the potential of prolame as an antidepressant steroid with equivalent actions to E2. Psychoactive properties of 17β-AEs in combinations with reduced adverse effects on coagulation, suggest that 17β-AEs may be a good alternative replacement therapy for women with symptoms associated with menopause.

Topics: Amino Alcohols; Animals; Anticoagulants; Anxiety Disorders; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrenes; Exploratory Behavior; Female; Motor Activity; Ovariectomy; Psychotropic Drugs; Rats, Wistar

Estrogen therapy may produce antidepressant-like actions, but the side effects, such as thromboembolic events, may restrict its use among women. The 17β-aminoestrogens (AEs) [prolame [17β-(3-hidroxy-1-propylamino)-1,3,5(10)-estratrien-3-ol)], butolame [17β-(3-hidroxy-1-butylamino)-1,3,5(10)-estratrien-3-ol)], and pentolame [17β-(5-hidroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol)] induce estrogenic and anticoagulant actions, effects that could prove advantageous in an estrogen therapy; however, their antidepressant-like effects have not been described. The objective of this study was to determine the effect of these 17β-AEs (prolame, butolame and pentolame) in the forced swimming test (FST), an animal model sensitive to antidepressant drugs, and to establish the role of estrogen receptors in such actions. Ovariectomized female rats treated with prolame (10-200 μg/rat) showed a reduction in immobility and an increase in active behaviors in the FST, while this effect was not produced by butolame and pentolame (10-200 μg/rat). The antidepressant-like effect of prolame was similar to that of 17β-estradiol (E2, 5-20 μg/rat), sharing with it a biphasic profile but at higher doses. Antidepressant-like actions of prolame and E2 were not associated with changes in locomotor activity. With respect to a control group tamoxifen (15 mg/kg) by itself produced no changes in all behavioral evaluations, but canceled the antidepressant-like effect of prolame and E2. It is concluded that estrogen receptors participate in antidepressant-like effect of both estrogens in the FST. Antidepressant-like activity of different AEs is discussed considering their differences in chemical structure and the schedule used. Our results show additional central actions of prolame besides its pro-sexual, anti-coagulant, estrogenic and anxiolytic activity.

Topics: Amino Alcohols; Animals; Antidepressive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrenes; Estrogen Antagonists; Estrogens; Female; Motor Activity; Movement; Rats; Rats, Wistar; Receptors, Estrogen; Swimming; Tamoxifen

17beta-aminoestrogens (AEs) produce anticoagulant effects in rats contrastingwith 17beta-estradiol (E2) procoagulant effects, their estrogenic effects are similar to E2, decreasing serum luteinizing hormone (LH), increasing uterine weight (Uw), activate transcription through the ERalpha and ERbeta receptors and pentolame induces progesterone (P) receptors in the anterior pituitary of ovariectomized (Ovx) rats similarly to E2, suggesting possible effects on female rats' sexual behavior. This work evaluated the AEs prolame, butolame, pentolame compared to E2 and estradiol benzoate (EB) as facilitators on the rat lordotic behavior. Dose-response curves were performed in rats by single subcutaneous (s.c.) injection (timezero) of: E2 (approximately 0.3, 3, 30, 60, 300 microg/kg); EB (approximately 0.4, 4, 40, 80, 400 microg/kg); prolame, butolame, pentolame (approximately 40, 400, 2000 or 4000 mg/kg), vehicle (corn oil; 300 microL/day; approximately 1.2 mL/kg) as control; 24 h after, P (1 mg/rat in 100 microL of corn oil; approximately 4 to 5 mg/kg) was administered, and 5 to 7 h later LQ was evaluated (number of lordosis displays/number of mounts x 100). E2, EB and AEs followed by P administration, induced lordosis in a dose-dependent manner. Prolame induced an LQEmax of 92, butolame85, EB 81, pentolame 44 and E2 43. The most potent was EB (LQED50 of 4.1 +/- 0.5 microg/kg); then E2 10 microg +/- 2.2/kg; prolame 268 +/- 19 microg/kg; butolame 402 +/- 21 microg/kg, and pentolame 1037 +/- 28 microg/kg. The AEs LQ potency decreases as length substitution on the amine group in C-17 increases. AEs LQDE50 values correlate with previous Uw DE50, LH ID50 and binding studies indicates mediation of the response by estrogen receptors. AEs facilitate sexual behavior of Ovx rats as partial estrogenic agonists.

Topics: Amino Alcohols; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Estradiol; Estradiol Congeners; Estrenes; Female; Male; Posture; Progesterone; Rats; Rats, Wistar; Sexual Behavior, Animal; Statistics, Nonparametric

17beta-aminoestrogens (AEs) decrease luteinizing hormone levels, increase uterine weight, activate transcription through ERalpha and ERbeta receptors and induce progesterone receptor expression in the anterior pituitary. This work evaluates the influence of single and multiple administration of a homologous series of the AEs: prolame, butolame and pentolame on rat female sexual behavior to explore their capability of inducing lordosis by themselves. In a reversed cycle the animals received one or three subcutaneous (s.c.) injections at 8:00 hr of: 7.5 microg E2/day (approximately 30 microg/kg), or 10 microg BE/day (approximately 40 microg/kg), or 1 mg/day prolame, butolame, pentolame (approximately 4000 microg/kg), or 300 microL/day of corn oil (approximately 1.2 ml/kg). Twenty-four hr following treatment, progesterone (P; 1 mg/0.1 ml of corn oil/rat) was administered; and 5 to 7 hr later, rats were tested for sexual receptivity and the lordosis quotient (LQ) was estimated (number of lordosis displays/number of mounts x 100). Single administration by themselves did not facilitate lordosis, 24 hr after the second injection, AEs-LQs values were: 24, 30, 21, E2 = 13 and EB = 11. administrations of three AEs increased LQs to: 48, 50, 45 E2 = 33 and EB = 57. The sequential P administration facilitated lordosis; after one injection: LQs 50-90 (p<0.01), meanwhile E2 and BE inducing LQs of 43 and 81 respectively. After the second and third injections and P administration the AEs LQs were 92-100 (p<0.01) similarly to E2 (95; p<0.01) and BE (96; p<0.01). The facilitation of sexual behavior by AEs was time and dose-dependent.

Topics: Amino Alcohols; Animals; Estradiol; Estrenes; Female; Male; Rats; Rats, Wistar; Sexual Behavior, Animal

Estrogens have been associated with thromboembolic events. Our group has described the anticoagulant effect of 17 beta-aminoestrogens in rodents, potentially new alternative estrogenic agents without thrombogenic risk. This work compares the contrasting effects of estradiol and the 17 beta-aminoestrogens (prolame, butolame, and pentolame) on blood clotting time. Ovariectomized CD1 mice received a single injection of 17beta-aminoestrogens, estradiol (20 to 80 mg/kg), or vehicle. Estradiol decreased blood clotting time from -10% to -25% (48 h; P<0.01) and 17 beta-aminoestrogens increased it, differing in latency (approximately 12 h; +48%, P<0.01) and duration (approximately 72 h +58%, P<0.01). In male Wistar rats, similar effects (pentolame +45%; estradiol -31%; P<0.01) were observed 48 h after five consecutive daily injections of 1000 microg/animal/day. The maximum procoagulant effect of estradiol was obtained after 72 h with 10 microg/animal/day (-45%; P<0.01). 17 Beta-aminoestrogens always produced opposite effects to those of estradiol on blood coagulation.

Topics: Amino Alcohols; Animals; Blood Coagulation; Dose-Response Relationship, Drug; Estradiol; Estradiol Congeners; Estrenes; Female; Male; Mice; Ovariectomy; Rats; Rats, Wistar

Administration of exogenous estrogens has been associated with an increase of thromboembolic events. The 17 beta-aminoestrogens produce anticoagulant effects contrasting with the procoagulant effects of the natural occurring estradiol in rodents. This work compares the estrogenic effects induced by 17 beta-aminoestrogens prolame, butolame, pentolame, and estradiol in vivo models. Dose-response curves were performed using immature CD1 mice and Wistar rats. The animals were injected with estradiol or 17 beta-aminoestrogens (0.01 to 1000 microg/kg), or vehicle. The uterine wet and dry weights were determined. The 17 beta-aminoestrogens increased uterine weight in a dose-dependent manner. The uterotrophic effect produced by estradiol induced lower ED50 (6.5 and 4 microg/kg) and higher E(max) values (+523-350%) in mice as compared with those from the rat, indicating more susceptibility of the mice model. The 17 beta-aminoestrogens are partial estrogenic agonists with a relative uterotrophic effect of estradiol (100%) from 9-86%. Only the ED50 values of 17 beta-aminoestrogens in CD1 mice showed a direct correlation to the length of the amine group substitution in C-17 since their efficacy and potency were in the order: prolame>butolame>pentolame.

Topics: Amino Alcohols; Animals; Dose-Response Relationship, Drug; Estradiol; Estradiol Congeners; Estrenes; Female; Mice; Organ Size; Rats; Rats, Wistar; Uterus

Topics: Amino Alcohols; Animals; Anticoagulants; Blood Coagulation; Dose-Response Relationship, Drug; Estradiol; Estradiol Congeners; Estrenes; Female; In Vitro Techniques; Male; Mice; Ovariectomy; Rats; Structure-Activity Relationship; Whole Blood Coagulation Time

Estrogenic activities of the two 17beta-aminoestrogen (AE) derivatives, prolame and butolame, were studied upon coagulation, serum luteinizing hormone (LH) and uterine weight, including endometrial morphology in castrated female rats. We have also investigated the ability of these two compounds, as well as another AE pentolame, to activate transcription through the estrogen receptor alpha (ERalpha) and the estrogen receptor beta (ERbeta). Administration of prolame and butolame to castrated animals increased significantly (P < 0.01) the mean clotting time when compared with that obtained in the group of control animals. Butolame was a more potent anticoagulant than prolame (P < 0.01), as judged by their corresponding IC(50) (5.4 +/- 0.65 and 66.6 +/- 2.57 micro;g/animal, respectively). In contrast, estradiol significantly shortened blood clotting times (P < 0.005). Both prolame and butolame caused a significant inhibition of serum LH levels (EC(50) 8.10 +/- 0.79 and 17 +/- 64 microg/animal, respectively), and restored castration-induced reduction in uterine weight of ovariectomized rats (EC(50) 4.14 +/- 1.57 and 17.0 +/- 1.78 microg/animal, respectively). In terms of the effects of prolame, butolame and pentolame in transient transfection assays, all the three AE activated ER dependent reporter gene expression, however, only at high concentrations. Prolame had the highest activity followed by butolame and pentolame. Induction of transcription by these compounds was preferentially mediated through the ERalpha, especially in the case of pentolame where little, if any, activation occurred through the ERbeta. None of the compounds showed antagonistic activities through either ER subtype. The overall data suggest that modifications in the structure and length of the amino-alcohol side-chain at C-17 might have an impact on the affinity and estrogenic intrinsic properties of AE at the level of diverse target tissues.

Topics: Amino Alcohols; Animals; Anticoagulants; Estradiol Congeners; Estrenes; Female; HeLa Cells; Humans; In Vitro Techniques; Luteinizing Hormone; Ovariectomy; Rats; Rats, Wistar; Receptors, Estrogen; Transcriptional Activation; Uterus