Pharmacological characterisation of a new oral GH secretagogue, NN703

NN703 is a novel orally active GH secretagogue (GHS) derived from ipamoreli n, NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect i s inhibited by known GHS antagonists, but not by a GH-releasing hormone ant agonist. Binding of S-35-MK677 to the human type 1A GI-IS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected, NN70 3 was also able to inhibit the binding of S-35-MK677. However, the observed K-i value was lower than expected, as based on the observed potencies rega rding GI-I release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency when compared with GHRP-6 and MK677, than that observed in rat pituitary cells, The effect of i.v. administration of NN703 on GH and cortisol release was s tudied in swine. The potency and efficacy of NN703 on GH release were deter mined to be 155 +/- 23 nmol/kg and 91 +/- 7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown. The effect of NN703 on GH release after i.v, and oral dosing in beagle dogs was studied. NN703 dose-dependently increased the GH release after oral ad ministration. At the highest dose (20 mu mol/kg), a 35-fold increase in pea k GH concentration was observed (49.5 +/- 17.8 ng/ml, mean +/- S.E.M.). Aft er a single i.v. dose of 1 mu mol/kg the peal; GH plasma concentration was elevated to 38.5 +/- 19.6 ng/ml (mean I S.E.M.) approximately 30 min after dosing and returned to basal level after 360 min, The oral bioavailability was 30%, The plasma half-life of NN703 was 4.1 +/- 0.4 h, A long-term biological effect of NN703 was demonstrated in a rat study, whe re the body weight gain was measured during a 14-day once daily oral challe nge with 100 mu mol/kg. The body weight gain was significantly increased af ter 14 days as compared with a vehicle-treated group, In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, hut has a different receptor pharmacology. NN703 induced GI-I release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH spe cificity in swine and significantly increased the body weight gain in rats.