Raun K, Hansen B S, Johansen N L, Thøgersen H, Madsen K, Ankersen M, Andersen P H
Department of GH Biology, Novo Nordisk A/S, Måløv, Denmark.
Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552.
The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1. In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor. In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). In conscious swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED50 for GH release. In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.
本文描述了一种新型强效生长激素（GH）促分泌素——伊帕莫林的研发及药理学特性。伊帕莫林是一种五肽（Aib-组氨酸-D-2-萘丙氨酸-D-苯丙氨酸-赖氨酸-NH2），在体外和体内均表现出高促生长激素释放效能和功效。作为一项重大化学项目的成果，伊帕莫林是在一系列缺乏生长激素释放肽（GHRP）-1中心二肽丙氨酸-色氨酸的化合物中被鉴定出来的。在体外，伊帕莫林从原代大鼠垂体细胞释放生长激素的效能和功效与GHRP-6相似（EC50 = 1.3±0.4nmol/l，Emax = 85±5%，而GHRP-6为2.2±0.3nmol/l和100%）。使用GHRP和生长激素释放激素（GHRH）拮抗剂进行的药理学分析清楚地表明，伊帕莫林与GHRP-6一样，通过类似GHRP的受体刺激生长激素释放。在戊巴比妥麻醉的大鼠中，伊帕莫林释放生长激素的效能和功效与GHRP-6相当（ED50 = 80±42nmol/kg，Emax = 1545±250ng GH/ml，而GHRP-6为115±36nmol/kg和1167±120ng GH/ml）。在清醒猪中，伊帕莫林释放生长激素的ED50 = 2.3±0.03 nmol/kg，Emax = 65±0.2 ng GH/ml血浆。同样，这与GHRP-6非常相似（ED50 = 3.9±1.4 nmol/kg，Emax = 74±7ng GH/ml血浆）。GHRP-2表现出更高的效能但更低的功效（ED50 = 0.6 nmol/kg，Emax = 56±6 ng GH/ml血浆）。在猪中研究了生长激素释放的特异性。所测试的生长激素促分泌素均未影响促卵泡激素、促黄体激素、催乳素或促甲状腺激素的血浆水平。给予GHRP-6和GHRP-2均导致促肾上腺皮质激素和皮质醇血浆水平升高。非常令人惊讶的是，伊帕莫林释放促肾上腺皮质激素或皮质醇的水平与生长激素释放激素刺激后观察到的水平没有显著差异。即使在比生长激素释放的ED50高200多倍的剂量下，对促肾上腺皮质激素和皮质醇血浆水平的这种影响缺乏也很明显。总之，伊帕莫林是第一种对生长激素释放具有与生长激素释放激素相似选择性的GHRP受体激动剂。伊帕莫林的特异性使其成为未来临床开发中非常有吸引力的候选药物。
