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Since the synthesis of the growth-hormone (GH)-releasing hexapeptide, GHRP-6, a potent growth-hormone secretagogue (GHS) in the early 1980s, other peptidyl derivatives, GHRP-1, GHRP-2 and hexarelin, which have different GH-releasing potencies, have been developed. These peptides act synergistically with GH-releasing hormone (GHRH) in vivo, and additively in vitro, on GH release through their interaction with GHS-R1a, a G-protein-coupled receptor that was cloned from mammalian pituitary in 1996 [1]. The identification of this receptor led to the discovery of its natural ligand, ghrelin, which is an acylated, 28-amino-acid peptide. The role of ghrelin in the control of GH release has been documented extensively [2]. Studies on the distribution of mRNA that encodes ghrelin and GHS receptors reveal that they are expressed widely in peripheral tissues. This indicates that GHSs have actions on peripheral targets other than GHRH neurons and pituitary somatotropes. Several recent reviews summarize the discovery and characteristics of GHS receptors [3] and ghrelin [4]. In this review we focus on the cardiovascular actions of ghrelin and synthetic GHSs.
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A review is presented on progress in the research of stimulatory inputs that regulate growth hormone secretion, including recent results on the action of the hypothalamic peptides growth-hormone releasing factor (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP), as well as that of both peptidic (growth hormone-releasing hexapeptide; GHRP-6) and non-peptidyl (L-163,255) synthetic GHSs on somatotrope cell function.
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It is becoming increasingly clear that the previously accepted model proposed to explain the hypothalamic regulation of growth hormone (GH) release from pituitary somatotropes, that is, the dual regulation by one stimulatory factor, growth-hormone releasing factor (GHRH), and one inhibitory, somatostatin (SRIF), is becoming obsolete and has to be expanded to include novel players (Frohman et al., 1992; Giustina and Veldhuis, 1998; Peter and Chang, 1999; McMahon et al., 2001). In particular, two classes of compounds are emerging as likely candidates to regulate GH secretion. Namely, pituitary adenylate cyclase-activating polypeptide (PACAP; Miyata et al., 1989; Arimura and Shioda, 1995; Vaudry et al., 2000) and the family of synthetic GH secretagogues (GHSs; Smith et al., 1996a,b; Bowers, 1999), of which a probable endogenous counterpart, a peptide termed ghrelin, has recently been identified, cloned and characterized (Kojima et al., 1999). There is also increasing evidence that in addition to these new extracellular regulators, the mechanisms that operate inside the somatotrope to interpret and respond to the instructions conveyed by such multiple regulatory inputs also include signaling pathways that were previously considered unimportant for this cell type (French et al., 1990; Bluet-Pajot et al., 1993). In our laboratory, we use the porcine somatotrope as a model to investigate the complexity of the control of GH secretion and the mechanisms underlying such control. Here, we review our recent results on the action of the hypothalamic peptides GHRH and PACAP, as well as that of both peptidic (growth hormone-releasing hexapeptide; GHRP-6) and non-peptidyl (L-163,255) synthetic GHSs on somatotrope cell function.
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The development of GHSs began with the synthesis of peptide analogues of the enkephalins as synthetic ligands for the morphine receptor. However, a selection of these peptides also exhibited weak GH-releasing ability [2]. Through structural modification, a series of small peptides, known as growth hormone-releasing peptides (GHRPs)—including the heptapeptide GHRP-1 and the hexapeptides GHRP-2 and GHRP-6—were developed. The biological potency of GHRP-6, the first GHRP to display in vivo growth hormone-secreting ability [3], has been further enhanced with the development of new peptide analogues such as hexarelin [4]. Despite their high potency and stability, the GHRPs display low bioavailability (less than 1%) due to their poor absorption in the gastrointestinal tract [5]. They also exhibit low specificity, often causing the secretion of prolactin, ACTH and cortisol [6] in addition to GH. Using GHRP-6 as a template, a large number of non-peptidyl secretagogues (the GHSs) have now been developed to avoid these problems [7].
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An interesting tetrazole semi-success story can be told about Merck & Company's non-peptidyl growth hormone secretagogue l-692,429 (19, Fig. 7). In 1988, a program was started to identify small molecule peptidomimetics of the growth hormone releasing hexapeptide His-d-Trp-Ala-Trp-d-Phe-Lys-NH2 (GHRP-6), from which the biphenyltetrazole 17 was designated as a lead compound.45 Replacement of the 2′-carboxylic acid group with a series of isosteric replacements singled out primary carboxamide 18 and tetrazole 19 (l-692,429), which provided an increased in vitro potency from the micromolar range to low nanomolar concentrations. On the other hand, acidic isosteres such as sulfonamides and acyl sulfonamides were found to be only micromolar in potency.46 At this point l-692,429 (19) was nominated for participation in clinical trial studies, and has progressed as far as Phase I.47 (Note: ED50 is defined as the effective dose at which a 50% maximal growth hormone response was achieved in vitro. EC50 is defined as the effective concentration at which 50% of maximal growth hormone release was induced.) A short time later, SAR studies conducted by chemists at Novo-Nordisk determined that other heterocycles without an acidic functionality were even more potent than 19 (e.g., 21, 22 and N-methyltetrazole 20), leading the researchers to conclude that the relevant ionic interaction with the receptor involved a hydrogen bond acceptor functionality on the drug molecule.48 This makes intuitive sense that tetrazole 19, being slightly less acidic than carboxylic functionality of 17, would conversely be a better hydrogen bond acceptor. It was around this time that Merck researchers became aware of some serious problems with the oral bioavailability of candidate 19, which was determined to be about 2% as studied in beagle dogs.49 The acidic tetrazolic functionality in presence of a basic primary amine causes 19 to be zwitterionic in nature, resulting in poor oral absorption properties that contribute to low oral efficacy. Based on this complicating factor, ongoing work to develop appropriate functional group compatibility had concurrently identified the N-methylurea candidate 23 (l-739,943). This neutral compound was even more potent at 1 nM (GHRP-6 has a potency of 10 nM) and was found to have a greatly enhanced oral bioavailability of 24% (hexapeptide GHPR-6 has an availability by oral dose at less than 1%).50 Ultimately, however, Merck has progressed the candidate MK-0677 (24; l-163,191; Ibutamoren Mesylate) into Phase II clinical studies for the treatment of growth hormone deficiency.51 Based on the ‘privileged structure’ approach52 to discover leads for G-protein coupled receptors, the researchers grafted the spiroindane moiety onto the peptide portion of 19, resulting in the potent growth hormone secretagogue 24. Oral dosing with MK-0677 was shown to elevate levels of growth hormone in dogs as low as 0.125 mg/kg, and its oral bioavailability was estimated to be greater than 60%. Merck researchers attributed the excellent oral absorption of 24 to its lipophilicity (log P=3.0 for 24 vs 2.5 for 19) in combination with the good aqueous solubility of the mesylate salt.53
Figure 7. The role of l-692,429 (19) as a mid-stream success early in the development of MK-0677 (24).
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INTRODUCTION
Reduced growth hormone (GH) secretion is a cause of delayed physical development in children as well as a consequence of normal aging (1–8). Deficits in GH secretion can be attributed to pituitary and/or hypothalamic etiologies, with the most common cause being insufficient production and/or secretion of neuroregulatory hormones (9). Intrinsic pituitary defects can also reduce GH production and/or secretion. These principles apply to both GH deficient children and adults. Although the etiologies are disparate, GH deficiency states are almost universally treated with recombinant GH. Only very recently has GH releasing factor been approved for treatment of GH deficiency in children. However, its use as a therapeutic agent has been limited because of variability and unpredictability of growth response.
The progressive decrease in GH secretion during aging could result from several factors. Two of the most obvious are inadequate stimulation of the pituitary gland by hypophysiotropic factors, or degeneration of pituitary-based mechanisms for GH production or secretion. Of the two possibilities, it is most likely that decremental changes in the relationship of the pituitary with GH regulatory hormones of hypothalamic origin are the primary etiologic factors in age-related decline in GH secretion. This view seems inconsistent with many reports that state that the pituitary becomes refractory to stimulation during aging. There is general consensus GH secretion in response to GHRH stimulation in vivo declines with advancing age (1–8). Assuming that GHRH is the only stimulatory agent controlling GH secretion, this progressive decrement could result from several factors. One could be that prolonged reduction in pituitary stimulation by GHRH causes desensitization to the GH secretagogue because hormones often induce their own receptors. Support for reduced stimulation of the pituitary by GHRH comes from evidence that available or appropriate GH secretagogue decline during aging (10–12). GHRH responsivity in aging rats, however, was immediately restored by co-administration with GHRP (13), suggesting that age-related, reduced efficacy of GHRH may be due to the absence or insufficient concentrations of other, as yet undefined, endogenous co-secretagogue (for a detailed overview of this subject, see Ref. 14).
About two decades ago, a family of xenobiotic GH secretagogue was discovered which released GH by a mechanism different from GH releasing hormone (GHRH) (15). The prototypic compound for this xenobiotic GH secretagogue family was His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 or GH releasing hexapeptide (GHRP). GHRP potentiated the action of GHRH when both compounds were administered together; and the potency of GHRH was reduced by passive immunization (16). The reciprocal test was not possible because an endogenous ligand for GHRP has not been identified. The recent report of the identification of the receptor should aid in this effort (17). Because functional dependence of GHRP can be demonstrated by passive immunization against GHRH, the reverse may be true (GHRH activity may be influenced by an endogenous GHRP analog). This possibility that GH secretion may be controlled by more factors than GHRH and somatostatin has been suggested previously (18).
We hypothesize that GHRH and an endogenous analog to GHRP are complementary GH secretagogues that together provide appropriate stimulation of the pituitary gland to sustain normal GH production and release. Using this logic, GHRH and GHRP could be given alone, and in combination, to diagnose pituitary-based causes of inadequate GH secretion (19). The model (Figures 1 and 2) assumes that a “normal” response to GHRP (or GHRP-mimic) stimulation or GHRH requires the presence of its endogenous analog (i.e. GHRH or GHRP, respectively). A blunted response to either exogenous GH secretagogue is interpreted as indicating a deficiency of its endogenous complement (Figures 1B and 1C). Blunted responses to both exogenous GH secretagogues administered sequentially implies deficiencies of both endogenous complements (Figure 1D). This situation can be differentiated from inherent pituitary abnormalities, such as receptor or second-messenger mediated deficits, by a “normal” response to GHRH and GHRP co-administration. A blunted response following co-administration of both secretagogues would suggest inherent pituitary dysfunction, rather than inadequate endogenous stimuli.
Figure 1. Schematic representation of the hypothetical model in support of the complementary relationship of GHRH and the endogenous ligand for GHRP or GHRP nonpeptide mimic. See text for discussion of the hypothesis. GHX refers to GHRP or GHRP nonpeptide mimic.From Reference (21).
Figure 2. A three-step provocative pituitary function test using responses to sequentially administered and co-administered GH secretagogues as diagnostic parameters for determining the neuroendocrine basis of GH secretory dysfunction.From Ref. (19).
To test our hypothesis, we summarize in this report the following: (1) use of the diagnostic test in children with altered growth patterns, (2) use of the diagnostic test in healthy adults and aging subjects, (3) effectiveness of priming with GHRP in aging men to address potential therapy of GH secretagogue(s) in “normal” aging.
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More than two decades ago, Cyril Bowers and his group synthesized a series of enkephalin-derived peptides that stimulated GH release in vitro, but lacked in vivo activity (Bowers et al., 1977). Bowers’ group further modified these peptides based on conformational energy studies and structure-activity relationship 2 years before the isolation of the hypothalamic peptide GHRH, thus enabling the synthesis of a GH-releasing hexapeptide, termed GHRP-6, with a neat ability to specifically release GH in vivo and in vitro in a number of species, including rat, pig and human (Bowers et al., 1984, 1990; Doscher et al., 1984). The hexapeptide subsequently served as a model to design and synthesize a series of peptidic (GH-releasing peptides, GHRPs) and non-peptidic compounds that shared the ability of releasing GH, and were therefore termed growth hormone secretagogues or GHSs (Deghenghi, 1996; Smith et al., 1996a,b; Wyvratt, 1996). The availability of non-peptidic GHSs that, like L-163,255, possess high oral bioactivity and low toxicity (Gertz et al., 1993; Chang et al., 1996) enhanced the possible clinical significance of these compounds, thereby attracting more interest to this research field. Moreover, the discovery in 1996 of the receptor specific for GHSs and its abundance in the pituitary and hypothalamus in human, pig and rat (Howard et al., 1996; McKee et al., 1997; Yokote et al., 1998) strongly suggested the existence of a natural analogue of the synthetic GHSs. Indeed, in December 1999, a 28-amino-acid-residue peptide that appears to be the endogenous ligand for this heretofore orphan receptor was isolated, cloned and characterized from rat and human stomach and was named ghrelin (Kojima et al., 1999).
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Assessment of growth hormone reserve
There are several biochemical tests that are used in clinical practice to confirm growth hormone deficiency (GHD). The clinical features of GHD are non-specific, and the different GH stimulation tests have different degrees of ability to stimulate GH release. For this reason, there continues to be debate about the most appropriate test and what extent of GH response constitutes true deficiency.
Insulin stress test
The insulin stress test (IST) remains the gold standard test of GH deficiency. In adults, a peak GH response to adequate hypoglycaemia (serum glucose <2.2 mmol/L) of >7 μg/L indicates a normal GH reserve, whilst a peak GH <3 μg/L, as defined by the UK National Institute for Health and Care Excellence (NICE), indicates severe deficiency. In children, a peak GH <6.7 μg/L after two provocative tests supports a diagnosis of growth hormone deficiency, although only one dynamic test is required in children with known hypothalamo–pituitary disease. The IST is unpleasant for patients and requires close medical supervision as it is potentially hazardous and is contraindicated in ischaemic heart disease and epilepsy. As well as being a reliable GH stimulus, the IST is also a good assessment of ACTH reserve so it a useful way of assessing GH and ACTH reserve simultaneously.
Children of both sexes may show subnormal GH responses to hypoglycaemia (and other dynamic tests) in the years immediately preceding puberty (objectively when the bone age is > 10 years). At the present time, there is no consensus with respect to the practice of ‘priming’ with gonadal steroids prior to such tests.
Other pharmacological tests
The glucagon test can be useful in the assessment of GHD when an IST is contraindicated, but it is a less reliable stimulus of GH and a poorer test of ACTH reserve than the IST, and its mechanism of action is not well understood. The criteria for diagnosing GHD in the glucagon test are the same as for the IST described above.
Other provocative tests of GH reserve include the GH-releasing hormone (GHRH) + arginine and GHRH + GH-releasing hexapeptide (GHRP-6) test, both of which have now been evaluated in large numbers of patients. The GHRH + arginine test may be particularly useful for young patients with radiation-induced GHD as occasionally the IST can give false negative results. Because GHRH + arginine is a more powerful GH stimulus, the cut-off point for diagnosing GHD is <9 μg/L.
In an attempt to avoid an IST, a variety of other pharmacological tests of GH reserve have also been used, particularly in children, including clonidine (0.15 mg/m2) and arginine infusion (0.5 g/kg). Use of these tests tends to be a matter of local preference; all are associated with rather variable responses and the peak GH values used to diagnose deficiency vary from laboratory to laboratory.
Exercise testing
Growth hormone is released during exercise and some laboratories have used an exercise test to assess GH reserve. Intensive, well controlled exercise (bicycle ergometer or treadmill) may exclude GH deficiency (by a peak GH response >6.7 μg/L), but less well controlled exercise (‘run up and down the stairs’) is unreliable.
Assessment of physiological growth hormone secretion
Because GH is secreted in a pulsatile fashion with increased pulses at night, serial blood tests, which can be done overnight or over 24 h, can be used to monitor the frequency and amplitude of GH pulses. Because this approach is labour intensive, requiring hospital admission with multiple blood samples, it is mainly a research tool.
Measurement of urinary GH is not part of routine clinical practice because of its low concentration in urine, but sensitive assays may make this possible in the future, particularly for the surveillance of GH replacement therapy.
Insulin-like growth factor 1 is produced by the liver in response to GH and, although measurement of its concentration is a useful diagnostic adjunct to provocative GH stimulation tests, it should not be used alone to diagnose GHD. However, the finding of a low IGF-1 in patients with three or four other pituitary deficiencies makes the likelihood of GHD sufficiently high that a formal provocative test may not be necessary.
Re-evaluation of GH status in young adults
In patients with isolated GHD that developed in childhood, it can be difficult to know whether GH replacement should be continued into adulthood. Patients with genetic hypopituitarism or multiple hormone deficiencies are highly likely to need to continue GH replacement. However, it may be able to be discontinued in patients with isolated or less severe GHD. In this situation, patients are re-tested during the period of transition between childhood and adulthood and the current consensus guidelines suggest a cut-off of <6 μg/L during an IST to indicate a continuing need for GH replacement. In this situation, the presence of clinical symptoms can also help the decision about whether to continue GH, which is best done by evaluation of the Adult Growth Hormone Deficiency Assessment (AGHDA) score. Consensus guidelines suggest that young adults with GHD should continue GH until the age of 25 years, when peak bone mass is likely to have been achieved.
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With the cloning of the GHS receptor, the early vision of Cyril Bowers in which GH-releasing hexapeptides were considered to represent a new physiological system implicated in the regulation of GH secretion has been confirmed. GHSs, administered alone or in combination with GHRH, are effective probes for understanding the normal and pathological regulation of GH in humans, and they might become safe and effective tests for the diagnosis of GH deficiency in both children and adults. Although long-term studies under strictly controlled conditions and with more subjects over longer periods are needed to determine dosages and to optimize administration, the data available suggest that the administration of selective GHSs in therapeutic schedules should not be associated with significant side effects. This illustrates the important potential of this new class of GHSs in the clinical setting.
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6.1 GHS-R1a ligands derived from enkephalin analogs and their SAR (structure-activity relationship) studies
Fundamental achievement of Bowers and the colleagues [142] on enkephalin analogs provided the base for the development of many magnificent compounds by many world leading pharma companies. They described a synthetic pentapeptide DTrp2 (Tyr-DTrp-Gly-Phe-Met-NH2) that had the potential to trigger the GH secretion from rat pituitary gland in vitro [143]. The first Gly of the natural opiate Met-enkephalin (Tyr-Gly- Gly-Phe-Met) was substituted with the nonproteinogenic DTrp2 in this compound.
Hexapeptide GHRP-6 growth-hormone-releasing peptide (GHRP) is the first in vivo active compound in and out of animals [144]. The polar residues surround its tetrapeptide core: Lys., on the C-terminus and His, on the N-terminus [145–147].
Later on, a study [148] suggested that GHRP's treatment in human could replace the costly and daily painful administration of hrGH treatment. The finding of short peptides or pseudopeptides with the potential to release endogenous GH was a turning point in this area of research.
Many research groups developed several compounds that were synthesized from compound GHRP-6. The gradual trimming of GHRP-6 helped the researchers to finally identify the active pharmacophore necessary to maintain GH secreting activity. It consists of an amine group at N-terminal and two aromatic residues [149].
The first biologically active benzolactams was compound L 692 429 with 2–8% oral bioavailability in animals and EC50 value of 60 nM [150] (Fig. 5). Through the N-terminal amino acid modification [151], benzolactam alteration [152], biphenyl group replacement [153], and tetrazole functions substitution [154], several analogs were synthesized. Among them, L 692 585 compound was turned out to be more potent than GHRP-6 both in vitro (EC50 = 3 nM as compared to 10 nM for GHRP-6) and in vivo in triggering pituitary GH secretion [155].
Fig. 5. Schematic representation of structure activity relationship of different compounds originating from GHRP-6.
Compound L 692 400, the first known GHS-R1a antagonist, cannot trigger release of GH in vitro. It hampers the release of GH induced by internal agonists, while does not inhibit GHRH stimulated GH secretion [156].
Ibutamoren enhances GH secretion outside and inside the tissues with good pharmacokinetics features [157]. Many Ibutamoren analogs were developed where the C-terminal amide group was changed by a benzimidazole or tetrazole ring [158]. This replacement could probably increase their bioavailability with the possibility of less hydrogen bonding.
Clinical trials with Ibutamoren have also been conducted but no one has hit phase III (Table 1). A phase II trial on recovery from broken hipbone was stopped because of lack of efficiency and congestive heart failure [157]. The treatment of Alzheimer's disease, fibromyalgia, composition of the body, older adults functioning, and end-stage renal disease on hemodialysis with Ibutamoren was also studied [127].
Table 1. Pseudopeptide or peptidomimetic ghrelin receptor ligands with clinical trial phases.
Structure of compound Compound name /Clinical success Company name Anamorelin/Phase III of clinical trail Novo Nordisk/Helsinn Therapeutics Macimorelin/Phase II and Phase III Aeterna Zentaris Fehrentz, Martinez et al. Capromorelin/Phase II discontinued Pfizer TZP-102/Phase II Tranzyme Pharma Ibutamoren/Phase II Discontinued Merck Ulimorelin/Phase III Not -continued Tranzyme Pharma Pralmorelin/Phase II Kaken Pharma Ipamorelin/Phase II clinical trial. Discontinued. Novo NordiskHelsinn Relamorelin Phase III Terminated Wieslaw Bochenek Allergan
Through structure activity study, the similarly structured agonist (L-163,540) [159], and the characteristics of Ibutamoren were combined in dipeptide capromorelin (CP-424,391–18) [160] (Fig. 6). At C-terminal, Capromorelin has pyrazolinone-piperidine heterocycle function. It induces in vitro release of GH with an EC50 value of 3 nM, elicits cortisol levels and induces weight gain during long-term administration in rats [161]. Capromorelin's phase II clinical studies to determine its effect on functionally restricted and elderly persons have been discontinued [162].
Fig. 6. Scheme showing the structure activity relationship of compounds developed from GHRP-6.
L 162 752 was the first compelling compound with good oral activity selected from the spiropiperidine series. Chemical alterations like insertion of sulfonamide function and an O-benzyl-D-serine residue instead of the D-tryptophan residue increased its potency. Through the radiolabeling (35S) of this compound, L 163 19 (Ibutamoren or MK 0677) was utilized to describe GHS receptor GHSR1a [2,163].
MK 0677 agonist, can trigger GH release from pituitary gland, is a nonpeptide with low molecular weight chosen for clinical trial. It has high oral bioavailability in dog, an EC50 value of 1.3 nM, 0.3 nM of affinity towards GHS-R1a, and a half-life of 5 h [164]. It had successfully reached phase II development [165,166]. But its further proceeding in clinical trials was terminated because of its profile related safety issues [128].
Spiroindoline piperidine was used as a template to derive spiroindoline piperidine based GHS-R1a antagonists (Fig. 6) and the best analogue had Ki values < 100 nM [167].
Benzoazepine- and dihydroisoquinoline-based GHS-R1a ligands were also synthesized having IC50 values from 1 to 10 nM [168]. GHRP-6 analogs that show more in vitro potency than GHRP-6 are with a D-ß-naphthylalanine (Nal) group. They are more powerful when administrated in rats through subcutaneous route [169,170].
Another GHS-R1a agonist developed from GHRP-6 is peptide G-7134 (Fig. 8), with shortened sequence and lacks the C-terminal Lys [171]. One N-substituted glycine and two 2-naphthylalanine groups have increased its oral bioavailability and it is more potent in vitro as compared to in vivo conditions [172].
Another methodology adopted with the goal to get the compounds having good oral bioavailability, and lower molecular weight was to shorten the GHRP-1 [173]. Molecular modeling superimposition was performed between compound L 692 429 and GHRP-1 with the deletion of central sequence Ala-Trp. The presence of D-Ala instead of N-terminal L-Ala residue (NNC 260133, compound) has restored the in vivo activity of compound along with its in vitro activity. After the substitution of the same N-terminal residue with a α-aminoisobutyric function, compound Ipamorelin was derived. It has reached phase II clinical trials for the cure of gastrointestinal dysmotility [174]. N-methylation of the amide bonds [175] was used to develop new compounds. Tabimorelin (Fig. 8) is an example that was used in human with success [176]. However, it has a drawback of blocking the CYP3A4 activity [177].
Synthesis of compounds formulated on α-amino-isobutyryl piperidine pattern [178] and modification of C-terminal carboxamide function [179] are some other strategies adopted to improve pharmacokinetic properties of compounds.
Hexarelin is also derived from GHRP-6 (Fig. 7), and was synthesized by replacing “D tryptophan” (DTrp2) with chemically more stable 2-methyl-D-tryptophan (DMrp). The derived compound had a little bit enhanced potency than GHRP-6 outside [147] and inside [147,180,181] the tissue. Its toxicity is lower than GHRP-6 and is proved to be one of the most popular GHRPs. Hexarelin is active in human [182–184] even when administered orally, with less than 1% bioavailability [180], and is orally not active in a dog species [180,184].
Fig. 7. Structure activity relationship of compounds derived from GHRP-6.
Fig. 8. Representation of structure activity relationship of compounds starting from GHRP-6.
Hexarelin treatment can cause a minor increase in prolactin (PRL) and considerable increase in the levels of cortisol, and Adrenocorticotropic hormone (ACTH) depending upon the route of administration [180,182]. Treatment with hexarelin exhibited increased cardiac output [185], and IGF-1-mediated anabolic effects with the increase in linear growth velocity, body weight, and head circumference [186].
Alexamorelin is an analogue of hexarelin containing an extra N-terminal Ala, EP-80317 with an altered N-terminus, and D-Lys located at 3rd position [187]. Compared to hexarelin in human, alexamorelin triggers the more release of cortisol, aldosterone and ACTH while PRL and GH levels are comparable [188].
There is a list of hexarelin-derived analogs. They have one or more unnatural amino acids and the pharmacophores in most of them are DTrp, DMrp, and D2Nal aromatic residues. For example, EP 40 737 prompts a much higher GH response as compared to hexarelin [181]. EP 51 389 is synthesized after downsizing of hexarelin sequence and is used as a guide analogue for novel GHRPs. C-terminal Lys –NH2 is absent in EP 51 389 (Fig. 7) and shorter but sometimes highly potent peptides are developed from it. A basic N-terminal residue, 2- aromatic core residue and a gem-diamino moiety at the C-terminus contribute to their structures [189].
Compound JMV 1843 (Fig. 7) was synthesized from EP 51 389 by introducing a formylated gem-(D)-diaminotryptophan at C-terminal region residue [190]. Being a strong in vitro hGHS-R1a agonist [191], it displayed more response to release GH as compared to hexarelin in rats, bioavailable in dogs, and had high oral activity in human [192]. It has crossed stage III clinical trials for the assessment of adult growth hormone insufficiency. For therapeutic treatment of tumor-induced cachexia, it has reached stage II clinical trials.
Structure-activity relationship studies discovered another ghrelin receptor antagonist compound called JMV 2959 (Fig. 7) [193,194]. It revealed the involvement of ghrelin and its receptor in intake of food, obesity, hyperactivity, addictive behaviors, and retinopathy [195].
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