Showing papers on "Growth hormone secretagogue published in 1999"
TL;DR: The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelIn, a peptide specifically releases GH both in vivo and in vitro.
Abstract: Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.
8,073 citations
TL;DR: It is shown that in healthy male volunteers, the effect of hexarelin on the HPA axis does not involve CRH, but may occur through the stimulation of AVP release.
Abstract: GH secretagogues (GHSs) act via specific receptors in the hypothalamus and the pituitary gland to release GH. GHSs also stimulate the hypothalamo-pituitary-adrenal (HPA) axis via central mechanisms probably involving CRH or arginine vasopressin (AVP). We studied the effects of hexarelin, CRH, and desmopressin, an AVP analog, on the stimulation of the HPA axis in 15 healthy young male volunteers. Circulating ACTH, cortisol, GH and PRL concentrations were measured for 2 h after the injection of hexarelin, CRH, or desmopressin alone and the combination of hexarelin plus CRH or hexarelin plus desmopressin. Symptoms during the tests were assessed by visual analog scales. Hexarelin significantly increased ACTH and cortisol release (area under the curve, 3,444 ± 696 ng/L·125 min and 45,844± 2,925 nmol/L·125 min, respectively), and this effect was augmented by the addition of CRH in a dose that on its own produces maximal stimulation (6,580 ± 1,572 ng/mL·125 min and 63,170 ± 2,616 nmol/L·125 min; P = 0.01 and 0.0...
100 citations
TL;DR: A mouse growth hormone secretagogue receptor has been isolated, cloned and sequenced in this paper, which is characteristic of the G-protein family of receptors and can be used to screen and identify compoumds which bind to the mouse GHS-R receptor, such compounds may be used in the treatment of conditions which occur when there is a shortage of growth hormone.
Abstract: A mouse growth hormone secretagogue receptor has been isolated, cloned and sequenced. This receptor is characteristic of the G-protein family of receptors. Mouse growth hormone secretagogue receptors may be used to screen and identify compoumds which bind to the mouse growth hormone secretagogue receptor. Such compounds may be used in the treatment of conditions which occur when there is a shortage of growth hormone, such as observed in growth hormone deficient children, elderly patients with musculoskeletal impairment and those recovering from hip fracture and osteoporosis. Targeted disruption of the mouse GHS-R gene may prove useful in elucidation of the mechanism of action and role of the growth hormone secretagogues in human and animal physiology.
64 citations
TL;DR: The first potent nonpeptidic ligands for somatostatin, luteinizing hormone-releasing hormone, glucagon and bradykinin receptors have been reported.
52 citations
TL;DR: In this paper, the expression of functional growth hormone secretagogue receptors (GHS-R) in a series of 30 human pituitary adenomas-six secreting GH, three GH-PRL, six prolactin (PRL), five adrenocorticotrophic hormone (ACTH), one thyroid stimulating hormone (TSH), four gonadotroph and five non-secreting adnomas.
Abstract: We examined the expression of functional growth hormone secretagogue receptors (GHS-R) in a series of 30 human pituitary adenomas-six secreting GH, three GH-PRL, six prolactin (PRL), five adrenocorticotrophic hormone (ACTH), one thyroid stimulating hormone (TSH), four gonadotroph and five non-secreting adenomas. By reverse transcriptase polymerase chain reaction (RT-PCR), the coexpression of the two GHS-R isoforms (Ia and Ib) was found in all the GH-, GH-PRL- and PRL-secreting adenomas, and only in two out of three corticotroph, two out of four gonadotroph and one out of five non-secreting tumours. They were absent in the TSH-secreting adenoma. The PCR products of GHS-R Ia and Ib were identical in size to those from two normal pituitaries. PCR cloning and sequencing of isoforms performed in two somatotroph adenomas revealed only two single, silent base mutations. Triple in-situ hybridization showed colocalization of GHS-R mRNA with messengers of GH and PRL, conjointly or separately, in individual cells of somatotroph, mammosomatotroph, and lactotroph adenomas. The presence of GHS-R mRNA in cells expressing PRL mRNA is emphasized. In cultured cells from six somatotroph and two mammosomatotroph adenomas, the powerful GHS MK-0677 stimulated GH release in a dose-dependent manner, with maximal effect at 6 h. Contrarily, when GHRH was applied, only three somatotrophs and two mamosomatotrophs were stimulated. In the two mammosomatotrophs, the PRL response to MK-0677 and to GHRH was similar to the GH response. An homologous desensitization of the GHS-R and the GHRH receptor was observed 24 h after a first stimulation by a single dose of the corresponding agonist. Heterologous desensitization was not observed. Interestingly, MK-0677 also stimulated, in a dose-dependent way, the hormone release of cells from all tested lactotroph and corticotroph adenomas. The existence of a functional expression of GHS-R in somatotroph, mammosomatotroph, lactotroph and corticotroph adenomas rises the question of the role played by GHS-R in pituitary adenomas, particularly those not engaged in GH secretion.
50 citations
TL;DR: This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary.
Abstract: It has been well established that the spiroindoline sulfonamide MK-0677 stimulates GH secretion from the pituitary both in vitro and in vivo. MK-0677 has also been shown to increase serum insulin-like growth factor I (IGF-I) and cortisol levels in vivo; these increases are assumed to be driven by the increased serum GH and ACTH levels, respectively. However, such increases could also be due to a direct stimulatory action of MK-0677 at the level of the liver and adrenal cortex. To address this possibility, we investigated whether MK-0677 increased IGF-I and cortisol levels in hypophysectomized dogs. Baseline GH, IGF-I, and cortisol responses to MK-0677 (1 mg/kg, orally) were initially determined. Hypophysectomy (hypox; n = 7) or sham surgery (sham; n = 5) was then carried out. Six days postsurgery, the GH and cortisol responses to MK-0677 were reevaluated in each dog. In addition, each dog was treated with porcine GH (PST; 0.1 IU/kg, s.c.) to confirm the responsiveness of the GH-IGF-I axis. The mean peak GH increases in response to MK-0677 in the presham dogs (83.7 +/- 19.2 ng/ml), post-sham dogs (108 +/- 26.2 ng/ml), and pre-hypox dogs (121.2 +/- 13.6 ng/ml) were not significantly different. Mean peak GH levels were unchanged after MK-0677 administration in the hypox dogs (2.3 +/- 0.7 ng/ml). Before surgery, serum IGF-I levels increased to 243 +/- 27 and 224 +/- 47 ng/ml in the sham and hypox groups, respectively, after MK-0677 administration. Surgery was associated with a marked (> or =50%) decrease in serum IGF-I levels. MK-0677 administration increased IGF-I levels in the sham dogs from 78 +/- 14 to 187 +/- 31 ng/ml, whereas IGF-I levels remained unchanged (17.7 +/- 2.4 ng/ml) in the-hypox dogs. PST treatment increased IGF-I levels in the sham dogs from 162 +/- 30 to 325 +/- 32 ng/ml. In the hypox dogs PST treatment restored IGF-I to physiological levels (from 17.7 +/- 2.4 to 199 +/- 41 ng/ml). Cortisol was increased after MK-0677 administration 3.7-fold in the pre-sham, 3.6-fold in the post-sham, and 3.6-fold in the pre-hypox dogs, but no increase was seen in the post-hypox dogs. ACTH GEL administration (2.2 U/kg, i.m.) to hypox dogs returned cortisol to normal physiological levels, demonstrating the functional integrity of the adrenal cortex. This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary.
29 citations
TL;DR: It is found, that incorporation of nonpolar peptidomimetic amino acids at the N-terminal can replace the Aib-His moiety and lead to compounds with high in vitro potency with respect to their growth hormone secretagogue properties.
28 citations
TL;DR: In this paper, the chemistry of 2-piperazinones and the use of this building block to restrict the conformational freedom of the growth hormone secretagogue NN703 (currently in clinical development) were discussed.
27 citations
Patent•
31 Aug 1999TL;DR: A growth hormone secretagogue is useful for enhancing the return of patients to independent living status following acute deconditioning such as that which may result from immobilization, surgery, or major injury such as hip fracture as mentioned in this paper.
Abstract: A growth hormone secretagogue is useful for enhancing the return of patients to independent living status following acute deconditioning such as that which may result from immobilization, surgery, or major injury such as hip fracture.
17 citations
Patent•
13 Jul 1999TL;DR: In this paper, a new family of receptors, growth hormone secretagogue-related receptors, which exhibit moderate sequence identity to both the GHS-R and the neurotensin receptor (NT-R) were introduced.
Abstract: This invention relates to a new family of receptors, growth hormone secretagogue-related receptors, which exhibit moderate sequence identity to both the growth hormone secretagogue receptor (GHS-R) and the neurotensin receptor (NT-R). These newly identified receptors are expressed in a diverse set of tissues. This invention also relates to nucleic acids encoding these receptors, and to the use of these receptors to identify ligands that modulate growth hormone release or other endocrine functions.
17 citations
TL;DR: In conclusion, L-163,255 in pigs has its primary effect at the level of the anterior pituitary, and fos activity in the hypothalamus of pigs showed marked fos activation compared to the controls.
Abstract: The activity of the growth hormone secretagog, L-163,255, on growth hormone (GH), growth hormone-releasing factor (GRF), and somatostatin (SRIF) levels was evaluated in a porcine model of hypophyseal portal blood (HPB) collection. Young, castrated pigs had HPB and jugular blood collected for approximately 300 min. The blood collection was divided into discrete periods: baseline (BL) approximately 180 min; GH response period (RSP) approximately 90 min; and positive control period following a GRF bolus, 30 min. RSP was divided into a dominant response period (DOM) and a tail (TL). The spontaneous relationship between HPB GRF and SRIF and peripheral GH during BL has been reported (Proc Soc Exp Biol Med 217:188-196, 1998). The apex of the GH pulse resulting from L-163,255 administration was nonrandomly associated (P < 0.05) with descending periods of SRIF troughs. Frequency and amplitude of GRF and SRIF pulses, and frequency and depth of SRIF troughs were not different between BL and the beginning of DOM (the 20-30 min of GH increase). GH AUC was significantly greater (P < 0.05) for DOM compared to BL and TL, and for TL compared to BL. GRF AUC tended to be greater (P < 0.1) for RSP compared to BL, but the majority of the increase was in the TL period. There were no significant differences in the SRIF AUCs between the sampling periods. Furthermore, in a separate experiment, fos activity (a marker of neuronal activation) in the hypothalamus of pigs was examined after either L-163,255 (1x or 4x), isotonic saline (control), or hypertonic saline (positive control) administration. There were no differences in fos activity in the GRF, SRIF, or CRH immunopositive neurons between L-163,255 treatment and control. The pituitaries of the L-163,255-treated pigs showed marked fos activation compared to the controls. In conclusion, L-163,255 in pigs has its primary effect at the level of the anterior pituitary.
01 Jan 1999
TL;DR: GHRP - unnatural toward the natural, C.Y. Bowers impervious peptides as GH secretagogues, R.D. Clark molecular analysis of the growth hormone secretagogue receptor, A.L. Dickson mechanisms of actions of growth hormone-releasing peptides and their analogues in vivo.
Abstract: GHRP - unnatural toward the natural, C.Y. Bowers impervious peptides as GH secretagogues, R. Deghenghi GHRP structure-activity relationship - an in vivo perspective, R. Clark molecular analysis of the growth hormone secretagogue receptor, A.D. Howard, et al intracellular GHRP signalling, C. Chen, I.J. Clarke the effects of GH-secretagogues on human pituitary cells in culture and on rat hypothalamic tissue, M. Korbonits, et al hypothalamic site and mechanism of action of growth hormone secretagogues, S.L. Dickson mechanisms of actions of growth hormone-releasing peptides and their analogues in vivo, C. Oliver, et al animal models of growth hormone deficiency as tools to study growth hormone releasing mechanisms, (L.A. Frohman, R.D. Kineman regulation of growth hormone (GH) pulsatility in humans, E.V. Dimaraki, A.L. Barkan hormonal activities of growth hormone secretagogues (GHS) across human lifespan, E. Arvat, et al effectiveness of growth hormone secretagogues in the diagnosis and treatment of GH secretory deficiency, B.B. Bercu, R.F. Walker does desensitization to growth hormone secretagogues occur?, A. Rahim, S.M. Shalet GHRPs in human obesity, J. Svensson, et al effects of growth hormone secretagogues on in vivo substrate metabolism in humans, N. Moller, et al growth hormone secretagogues - physiological role and clinical implications, C. Dieguez, et al growth hormone secretagogues in critical illness, G.H.A. Van Den Berghe growth hormone secretagogues in catabolic illness, R.C. Jenkins, R.J.M. Ross treatment of children with short stature by growth hormone secretagogues, Z. Laron therapeutic potential of GH secretagogues in adults, R.M. Nass, M.O. Thorner growth hormone secretagogue influences feeding behaviour in experimental animals, I. Wakabayashia, et al growth hormone secretagogues and sleep, A. Steiger hexarelin, a synthetic growth hormone secretagogue, exhibits protectant activity in experimental myocardial ischemia and reperfusion, F. Berti potential applications of growth hormone secretagogues, I. Shimon, S. Melmed.
TL;DR: The C-terminal of the orally active growth hormone secretagogue NN703 was changed to prepare analogues with inverse sulfonamides and inverse amides, which showed high activity in a in vitro rat pituitary model.
TL;DR: Systematic investigation of acyclic analogs of L-692,429, the prototype benzolactam growth hormone secretagogue, has helped to further define the structural requirements for the release of growth hormone from rat pituitary cells for this class of secretagogues.
TL;DR: The strength of focused combinatorial libraries is demonstrated and the pitfall in broad SAR exploration is confirmed by giving examples where selected fragments obviously show poor receptor interaction except in very defined structural arrangements.
Patent•
22 Nov 1999TL;DR: In this article, a process for preparing compounds of the Formula (See Formula I) was described, where R1, R2 and Pt are as defined in the specification, which are intermediates in the synthesis of certain growth hormone secretagogue compounds.
Abstract: This invention relates to a process for preparing compounds of the Formula (See Formula I) wherein R1, R2 and Pt are as defined in the specification, which are intermediates in the synthesis of certain growth hormone secretagogue compounds This invention further relates to processes for preparing the growth hormone secretagogues The invention also relates to the compound of Formula I wherein R1 is H, R2 is 2,2,2-trifluoromethyl and Pt is Boc
01 Jan 1999
TL;DR: The objective was to compare the GH-releasing action of GHRP-2 and GHRH alone and together to assess specific peptide, dosage, age, and sex dependencies.
Abstract: An earlier finding of the growth hormone-releasing peptides (GHRPs) was that they released GH more effectively in humans than in a number of different animal species, including rats, cows, pigs, sheep, rhesus monkeys, and chickens (1,2). To better appreciate the acute GH-releasing action of GHRP-2 and GHRH 1–44NH2, studies have been performed in normal younger and older men and women. The hypothesis pursued was that new insight into the actions of sex steroids or GHRP on GH release can be revealed from the acute GH-releasing action of GHRP-2 and GHRH in diverse clinical contexts. The objective was to compare the GH-releasing action of GHRP-2 and GHRH alone and together to assess specific peptide, dosage, age, and sex dependencies.
TL;DR: A new class of growth hormone (GH) secretagogues (GHS) has been developed and in rats, the GHS hexarelin exerts cardioprotective effects and in healthy obese men, oral GHS treatment increases fat-free mass.
Abstract: A new class of growth hormone (GH) secretagogues (GHS) has been developed. In rats, the GHS hexarelin exerts cardioprotective effects. In humans, GHS increase growth velocity in children with short stature/GH deficiency. In adults, a combined infusion of GH releasing peptide-2 and thyrotropin releasing hormone increases circulating concentrations of GH as well as that of insulin-like growth factor-I. In healthy volunteers, oral GHS administration reverses diet-induced catabolism, and in healthy obese men, oral GHS treatment increases fat-free mass. However, little is known about the possible direct effects of GHS and there are few long-term studies. Therefore, it is not yet possible to fully evaluate the use of GHS.
Patent•
18 Nov 1999TL;DR: In this article, a process for preparing compounds of the Formula wherein R1, R2 and Pt are as defined in the specification, which are intermediates in the synthesis of certain growth hormone secretagogue compounds.
Abstract: This invention relates to a process for preparing compounds of the Formula wherein R1, R2 and Pt are as defined in the specification, which are intermediates in the synthesis of certain growth hormone secretagogue compounds. This invention further relates to processes for preparing the growth hormone secretagogues. The invention also relates to the compound of Formula I wherein R1 is H, R2 is 2,2,2-trifluoromethyl and Pt is Boc.
TL;DR: The effects of MK‐677 treatment on serum levels of leptin, thyroid hormones and testosterone were determined and it was found that growth hormone treatment decreases total body fat while this effect has not yet been documented for the oral GH secretagogue MK-677.
Abstract: OBJECTIVE
Growth hormone (GH) treatment decreases total body fat while this effect has not yet been documented for the oral GH secretagogue MK-677. In the present study, the effects of MK-677 treatment on serum levels of leptin, thyroid hormones and testosterone were determined.
DESIGN
This was a randomized, double-blind, and parallel study. Twenty-four healthy obese males, 19–49 years of age, with body mass index (BMI) > 30 kg/m2 and a waist:hip ratio > 0.95, were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks.
RESULTS
MK-677 treatment increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment (P < 0.05 vs. placebo) but no significant change was observed at 8 weeks. An increase in serum free 3, 5, 3′-triiodothyronine (free T3) was not detected until 8 weeks of MK-677 treatment (P < 0.05 vs. placebo). Peak serum thyroid stimulating hormone (TSH) concentration after MK-677 administration was similar to that after placebo administration at initiation of treatment and at 2 weeks. At 8 weeks of MK-677 treatment, mean peak serum TSH concentration was increased (P < 0.05 vs. placebo) although it remained within the normal range. Serum peak values of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were similar after MK-677 and placebo administration. MK-677 treatment reduced serum total testosterone (P < 0.05 vs. placebo) although total testosterone/sex hormone-binding globulin (SHBG) ratio (an index of free testosterone) was not changed.
CONCLUSION
Treatment with the oral GH secretagogue MK-677 transiently increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment, and increased serum free T3 after 8 weeks. These results indicate that MK-677 treatment is able to affect circulating factors of importance for adipose tissue mass and fuel metabolism.
01 Jan 1999
TL;DR: Evidence is provided that, in the male rat, GH can feedback to the hypothalamus, altering the responsiveness of neurons involved in the central response to GHS, and that some arcuate nucleus neurons are not subject to the feedback effects of endogenous GH.
Abstract: Growth hormone secretagogues (GHS) administered systemically selectively induce growth hormone (GH) release from the pituitary and the expression of Fos protein in arcuate nucleus neurons. Both the co
Patent•
20 Jan 1999
TL;DR: The instant polymorphic forms have advantages over the other known forms of N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations as discussed by the authors.
Abstract: This invention is concerned with polymorphic forms of the compound N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate which is a growth hormone secretagogue that is useful in food animals to promote their growth thereby rendering the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, and to treat medical conditions which are improved by the anabolic effects of growth hormone. The instant polymorphic forms have advantages over the other known forms of N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperdin]-1'-yl)carbonyl]-2-(phenylmethyloxy)-ethyl]-2-amino-2-methylpropanamide methanesulfonate in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations. The present invention is also concerned with processes for preparing these polymorphic forms, pharmaceutical formulations comprising these polymorphic forms as active ingredients and the use of the polymorphic form of the compound and their formulations in the treatment of certain disorders.
TL;DR: A limited screen of several commercially-available and internally-produced lipases and esterases identified porcine liver esterase as a suitable biocatalyst for the enantioselective hydrolysis of a diester into its (S)-ester acid with high optical purity (99%).
01 Jan 1999
TL;DR: Growth hormone secretagogues are synthetic peptidyl and nonpeptidyl molecules that possess strong, dose-dependent, and reproducible GH-releasing activity in vivo in several species and in humans after intravenous, subcutaneous, intranasal, and oral administration.
Abstract: Growth hormone secretagogues (GHS) are synthetic peptidyl and nonpeptidyl molecules that possess strong, dose-dependent, and reproducible GH-releasing activity in vivo in several species and in humans after intravenous, subcutaneous, intranasal, and oral administration (1–4) In addition to GHRP-6, other members of the GHS family studied in humans include peptidyl analogs, such as GHRP-1 (a heptapeptide), GHRP-2 and Hexarelin (both hexapeptides), and nonpeptidyl GHRP mimetics, such as MK-0677, a spiroindoline, which shows high bioavailability and long-lasting effects after oral administration (1–4)
01 Jan 1999
TL;DR: Passive immunization studies have established that GRF and somatostatin control different aspects of the GH secretory pattern: GRF controls GH pulse amplitude and its release is a prerequisite for pulsatile GH secretion whereas som atostatin is important for regulating the period between pulses.
Abstract: Growth hormone (GH), like many other pituitary hormones, is released from the pituitary in a highly episodic manner. In the conscious male rat, the pulsatile pattern of GH secretion is particularly striking, with high amplitude pulses occurring regularly, once every 3–4 h (Tannenbaum & Martin, 1976). The pattern of GH secretion reflects a changing balance in the output of two neuroendocrine systems: the GH-releasing hormone (GRF) neurones, which stimulate GH secretion (Guillemin et al. 1982; Rivier et al. 1982) and the somatostatin neurones, which inhibit GH secretion (Brazeau et al. 1973). GRF and somatostatin are released into portal blood at the median eminence and are then transported to the anterior pituitary where they bind to different receptors on the somatotroph cells. Passive immunization studies have established that GRF and somatostatin control different aspects of the GH secretory pattern: GRF controls GH pulse amplitude and its release is a prerequisite for pulsatile GH secretion whereas somatostatin is important for regulating the period between pulses (see Jansson et al. 1985). Somatostatin also appears to be involved in the GH pulse generating mechanism, since a pulsatile pattern of GH secretion can be generated by an intermittent intravenous infusion of somatostatin, in which GH pulses occurred when delivery of somatostatin was interrupted for a short period every 3 hours (Clark & Robinson 1988).
01 Jan 1999
TL;DR: In this article, the Cterminal of the orally active growth hormone secretagogue NN703 was changed to prepare analogues with inverse sulfonamides and inverse amides.
Abstract: The C-terminal the orally active growth hormone secretagogue NN703 was changed to prepare analogues with inverse sulfonamides and inverse amides. The compounds showed high activity in a in vitro rat pituitary model.