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Analogs of the delta opioid antagonist TIPP with increased lipophilic character

机译：Delta阿片类拮抗剂Tipp与亲脂性特征的类似物

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The peptide hormone LHRH (LH releasing hormone) is liberated by hypothalamic neurons and regulates the release of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland. In 1971 Schally et al. [1] were able to isolate LHRH from hypothalamic extracts and to establish its amino acid sequence. The replacement of different amino acids then led to the discovery of highly active analogues like the superagonists, which are used clinically today in many hormone-dependent diseases. Paradoxically, by chronic administration these LHRH-agonists can also be used to suppress the gonadotropins, a mechanism which is based o nthe induction of a down-regulation of pituitary receptors. However, the administration of agnoists initially leads to a stimulatory effect on LH, FSH and sex steriod secretion, which might result in a "flare up" of the disease. The advantage of antagonistic analogues is the immediate onset of gonadal steroid suppression by competitive binding to the LH-RH receptors already after a single administration. So far the clinical development of LHRH-antagonists was delayed due to low potency, side effects such as edema due to histamine release and high dosage requirements [2]. With the synthesis of compounds like Nal-Glu or Antide these side-effects started to decrease. Major improvement was achieved by the new LHRH-antagonist Cetrorelix (INN). This antagonist is free of anaphylactoid effects and produced a strong suppression of gonadotropins [3]. This paper summarises results from the chemical, pharmacological and clinical development of Cetrorelix.
机译：肽激素LHRH（LH释放激素）由下丘脑神经元释放，并调节促性腺激素培氏素培养激素（LH）和卵泡刺激激素（FSH）的释放。 1971年Schally等人。 [1]能够从下丘脑提取物中分离LHRH并建立其氨基酸序列。更换不同的氨基酸然后导致了像超谓者那样的高活性类似物的发现，这些类似物在临床上使用许多激素依赖性疾病。矛盾的是，通过慢性施用，这些LHRH激动剂也可用于抑制促性腺激素，一种基于垂直受体的诱导的机制。然而，Angnoists的给药最初导致对LH，FSH和性甾体分泌的刺激作用，这可能导致疾病的“爆发”。拮抗性类似物的优点是通过竞争性结合到已经在单一给药之后的LH-RH受体的竞争结合即时开始。到目前为止，由于组胺释放和高剂量要求，LHRH-拮抗剂的临床开发延迟，诸如水肿等水肿等副作用[2]。通过合成NAL-Glu等化合物或抗抗体开始降低。新的LHRH-拮抗剂CetroreLix（Inn）实现了重大改进。该拮抗剂不含过敏反应作用，并产生强大的促性腺激素[3]。本文总结了CetroreLix的化学，药理和临床发展的结果。

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