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
35S-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 Ϯ 23 nmol/kg and 91 Ϯ 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 dosedependently increased the GH release after oral administration. At the highest dose (20 mmol/kg), a 35-fold increase in peak GH concentration was observed (49.5 Ϯ 17.8 ng/ml, mean Ϯ S.E.M.). After a single i.v. dose of 1 mmol/kg the peak GH plasma concentration was elevated to 38.5 Ϯ 19.6 ng/ml (mean Ϯ 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 Ϯ 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 mmol/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.
1 Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2 The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMS) as compared with 27 poor metabolizers (PMJ), but none of the ratios separated the two phenotypes completely. 3 There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample.The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: -0.20 and -0.27, P < 0.05).4 The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5 CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMS, meaning that they were genotyped correctly. One PM, was D6-wt/D6-B, another PMS had the genotype D6-wt/ and hence both were misclassified as EMS. The remaining 25 PMs were D6-AID6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2). Thus, the specificity for genotyping PMs was 100% and the sensitivity was 92.4%. 6 There were 198 apparently homozygous EMS (D6-wt/) and 98 heterozygous EMS (D6-wt/D6-A or D6-wt/D6-B). The sparteine metabolic ratio was lower and the hydroxylation ratios were higher in the homozygotes compared with the heterozygotes. However, for all of the ratios there was a considerable overlap between the two genotypes.
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