Hansen B S, Raun K, Nielsen K K, Johansen P B, Hansen T K, Peschke B, Lau J, Andersen P H, Ankersen M
Department of General Cell Biology, Health Care Discovery and Preclinical Development, Novo Nordisk A/S, Novo Nordisk Park DK-2760 Mâlev, Denmark.
Eur J Endocrinol. 1999 Aug;141(2):180-9. doi: 10.1530/eje.0.1410180.
NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. 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 is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist. Binding of (35)S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of (35)S-MK677. However, the observed K(i) value was lower than expected, as based on the observed potencies regarding GH 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 studied in swine. The potency and efficacy of NN703 on GH release were determined 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 administration. At the highest dose (20 micromol/kg), a 35-fold increase in peak GH concentration was observed (49.5+/-17.8 ng/ml, mean+/-s.e.m.). After a single i.v. dose of 1 micromol/kg the peak GH plasma concentration was elevated to 38.5+/-19.6 ng/ml (mean+/-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, where the body weight gain was measured during a 14-day once daily oral challenge with 100 micromol/kg. The body weight gain was significantly increased after 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, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.
NN703是一种源自伊帕莫林的新型口服活性生长激素促分泌素（GHS）。NN703以剂量依赖性方式刺激大鼠垂体细胞释放生长激素，其效力和效能与生长激素释放肽-6（GHRP-6）相似。已知的GHS拮抗剂可抑制该作用，但生长激素释放激素拮抗剂则无此作用。正如预期的那样，生长激素释放肽-6（GHRP-6）和MK677可抑制（35）S-MK677与稳定表达于BHK细胞上的人1A型GHS受体（GHS-R 1A）的结合。NN703也能够抑制（35）S-MK677的结合。然而，基于从大鼠垂体细胞释放生长激素的观察效力，所观察到的抑制常数（K（i））值低于预期。同样，与GHRP-6和MK677相比，NN703对这些细胞中GHS-R 1A诱导的肌醇磷酸周转的作用显示出较低的效力，这一效力低于在大鼠垂体细胞中观察到的情况。研究了静脉注射NN703对猪生长激素和皮质醇释放的影响。NN703对生长激素释放的效力和效能分别确定为155±23 nmol/kg和91±7 ng生长激素/毫升血浆。对于所有测试剂量的NN703，均观察到皮质醇水平较基础水平增加了50%，但未显示出剂量依赖性。研究了静脉注射和口服给药后NN703对比格犬生长激素释放的影响。口服给药后，NN703剂量依赖性地增加生长激素释放。在最高剂量（20微摩尔/千克）时，观察到生长激素峰值浓度增加了35倍（49.5±17.8纳克/毫升，平均值±标准误）。静脉注射单次剂量1微摩尔/千克后，给药后约30分钟生长激素血浆峰值浓度升高至38.5±19.6纳克/毫升（平均值±标准误），并在360分钟后恢复至基础水平。口服生物利用度为30%。NN703的血浆半衰期为4.1±
