Reverse Pharmacology

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Reverse pharmacology is the terminology proposed by Conn and Bowers in 1996 to describe the chemical biological approach utilised in accomplishing the development from unnatural GHRP to natural ghrelin. The first GHRP we developed was the DTrp2 pentapeptide listed in Table 3.

DTrp2 was only active in vitro and was low in potency, but released only GH and not prolactin, adrenocorticotropin (ACTH), luteinising hormone (LH), follicle-stimulating hormone (FSH) or thyroid-stimulating hormone (TSH). The four chemical classes of GHRPs that became chemical templates for us as well as other investigators were developed in the subsequent 3 years. Highly potent GHRPs have been developed from each of these four classes of GHRP chemical templates that are active in releasing GH in vivo. The chemistry of three of our highly potent GHRPs derived from the DTrp2LTrp4 chemical class is recorded in Table 4.

The comparative GH-releasing activity in humans of the three GHRPs (Table 3) relative to

Table 2a. 30-Day continuous subcutaneous infusion of 1 ^g/kg/h growth hormone-releasing peptide (GHRP)-2

Day

GH

AU&24 h (^g/l±SEM) IGF-1

IGF-II

Placebo

-3

824 ± 153

105 ±9

356 ± 14

GHRP-2

0

4544 ± 764a

173 ± 15a

357 ± 16

GHRP-2

14

1764 ± 198a

175 ± 16b

393 ± 36

GHRP-2

30

1699 ± 201b

177 ± 16a

369 ± 30

-

60

-

99 ± 14

333 ± 26

Age 64 ± 2.8, BMI 26 ± 1.1, n = 17, values are mean of single determinations at end of infusion, p value = a < 0.001,b < 0.01. IGF, insuline-like growth factor; GH, growth hormone

Table 2b. 30-Day continuous subcutaneous infusion of 1^g/kg/h growth hormone-releasing peptide (GHRP)-2

Day

IGF BP3

AU&24 h (Hg/l±SEM) IGF BP4

IGF BP5

Placebo

-3

2483 ± 207

545 ± 35

313 ± 16

GHRP-2

0

2937 ± 253

554 ± 23

393 ± 27c

GHRP-2

14

3677 ± 253b

542 ± 34

377 ± 30

GHRP-2

30

3462 ±311c

516 ±38

385 ± 21c

-

60

2623 ± 327

452 ± 44

324 ±10

Age 64 ± 2.8, BMI 26 ± 1.1, n = 17, values are mean of single determinations at end of infusion,p value = b < 0.01,c < 0.02. IGF, insuline-like growth factor

Table 3. In vitro active growth hormone-releasing peptides

(1976-1985)

Amino acid sequence

Abbreviation

TyrDTrp2GlyPheMetNH2

DTrp2

TyrAlaDTrp3PheMetNH2

DTrp3

TyrDTrp2DTrp3PheNH2

DTrp2'3

TyrDTrp2AlaTrp4DPheNH2

DTrp2LTrp4

activity of ghrelin and GHRP, which further underscores the independency and interdepend-ency of their in vivo actions.

The high potency, effectiveness and chemical stability of the GHRPs can be deduced by the results in Fig. 4, which reveal that GHRP-2 very effectively releases GH in normal men by various routes of administration. It is particularly of clinical interest that this release is increased by oral administration, even at the low dose of 10 mg. In each other and to GHRH is shown in Fig. 3. The results were notable in that while GHRH was at its maximal dosage, each of the unnatural GHRPs stimulated more GH release than GHRH alone. Therefore, these GHRPs were acting differently from GHRH to release GH. Parenthetically, it must be noted that intact endogenous GHRH is an absolute determinant of the in vivo GH-releasing

Table 4. In vivo active growth hormone-releasing peptides (GHRPs)

GHRP Amino acid sequence

GHRP-6 His1DTrp2Ala3Trp4DPhe5Lys6NH2 GHRP-1 Ala1His2D|3Nal3Ala4Trp5DPhe6Lys7NH2 GHRP-2 DAla1D|Nal2Ala3Trp4DPhe5Lys6NH2

Fig.3. Comparative GH responses to 1 ^g/kg intravenous bolus administration of GHRH 1-44NH2, GHRP-6, GHRP-1 and GHRP-2 in normal young men.Values are means ± SEM. (Modified from [1])

Fig.3. Comparative GH responses to 1 ^g/kg intravenous bolus administration of GHRH 1-44NH2, GHRP-6, GHRP-1 and GHRP-2 in normal young men.Values are means ± SEM. (Modified from [1])

contrast, when GHRPs are administered in high pharmacological dosages, as recorded in Fig. 4, ACTH/cortisol and prolactin release is increased via a hypothalamic action.

Thus, GHRP showed clinical potential in several ways: defining a pathway complementary to that of GHRH (vide infra); displaying oral activi ty; and having high potency. This potential was furthered when the ghrelin molecule was isolated and then validated as the natural GHRP hormone. The interesting 28 amino acid structure of ghrelin is shown below (Fig. 5).

As has been discussed (vide infra), the cova-lent linked octanoyl group addition to the Ser3

Fig.4. Route of administration of GHRP-2 in normal young men.Values are means ± SEM

amino acid side chain via an ester bond is a first in peptide hormone chemistry. The ghrelin molecule with the octanoic carboxylic acid is just as exciting biologically as it is chemically because the desoctanoyl ghrelin (without the octanoyl group attached) no longer binds to the ghrelin type 1a receptor. Thus, the octanoyl group is a critical determinant for attaining a complementary receptor conformation by the ghrelin molecule.

In spite of the very different chemistry of the unnatural GHRPs and natural ghrelin, each of these two very different classes of peptides binds with high affinity to the same natural GHS/GHRP/ghrelin receptor. This is further demonstrated by the results in Fig. 6, where both GHRP-2 and ghrelin have the same acute GH-releasing actions in normal young men alone and synergistically with GHRH [8]. Therefore, the bio-

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