Foreman M M, Fuller R W, Leander J D, Benvenga M J, Wong D T, Nelson D L, Calligaro D O, Swanson S P, Lucot J B, Flaugh M E
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
J Pharmacol Exp Ther. 1993 Oct;267(1):58-71.
LY228729 is a conformationally restricted tryptamine derivative with a carboxamide serving as a protophilic group to mimic the hydroxyl in serotonin (5-HT). LY228729 has high affinity for the 5-HT1A receptor, weak affinity for the 5-HT1D receptor and no significant affinity for other monoaminergic receptors studied. LY228729 was less effective than 5-carboxamidotrytamine in suppressing K(+)-evoked release of 3H-5-HT from parietal-occipital cortical slices from guinea pigs, which is in agreement with its weak 5-HT1D receptor affinity. LY228729 reduced hypothalamic 5-hydroxyindole-3-acetic acid levels and increased serum corticosterone levels in rats. LY228729 reduced hypothalamic 5-hydroxytryptophan accumulation after decarboxylase inhibition. LY228729 increased flat posture and lower lip retraction scores in rats at doses between 0.1 and 1 mg/kg s.c. (p.o. doses were 10 times higher) and these effects were blocked by (+/-) pindolol. LY228729 induced a hypothermic response in rats, which was blocked by (+/-) pindolol. These in vivo responses are characteristics of compounds with 5-HT1A agonist activity. In the preclinical efficacy models, LY228729 suppressed motion sickness responses in cats; decreased ejaculatory latency and the increased copulatory efficiency and rate in rats and increased punished responding at lower doses than it lowered unpunished responding in rats. Collectively, these results indicate that LY228729 is potent 5-HT1A agonist with bioavailability properties sufficient for clinical evaluation and with efficacy in preclinical models of anxiety, sexual disorders and motion sickness. Since the 5-HT1A agonists that have been studied previously have antidepressant activity, this indication will also be evaluated.
LY228729是一种构象受限的色胺衍生物，其羧酰胺作为亲质子基团，模拟血清素（5-羟色胺，5-HT）中的羟基。LY228729对5-HT1A受体具有高亲和力，对5-HT1D受体具有弱亲和力，对所研究的其他单胺能受体无明显亲和力。在抑制豚鼠顶枕叶皮质切片中钾离子诱发的3H-5-HT释放方面，LY228729的效果不如5-羧酰胺色胺，这与其对5-HT1D受体的弱亲和力一致。LY228729可降低大鼠下丘脑5-羟吲哚-3-乙酸水平，并升高血清皮质酮水平。在抑制脱羧酶后，LY228729可减少下丘脑5-羟色氨酸的积累。皮下注射剂量为0.1至1 mg/kg时（口服剂量高10倍），LY228729可提高大鼠的平伏姿势和下唇后缩评分，这些作用可被（±）吲哚洛尔阻断。LY228729可诱导大鼠体温过低反应，该反应可被（±）吲哚洛尔阻断。这些体内反应是具有5-HT1A激动剂活性的化合物的特征。在临床前疗效模型中，LY228729可抑制猫的晕动病反应；降低大鼠的射精潜伏期，提高交配效率和频率，并在比降低大鼠非惩罚性反应更低的剂量下增加惩罚性反应。总体而言，这些结果表明，LY228729是一种有效的5-HT1A激动剂，具有足以进行临床评估的生物利用度特性，并且在焦虑、性功能障碍和晕动病的临床前模型中具有疗效。由于先前研究的5-HT1A激动剂具有抗抑郁活性，因此也将对这一适应症进行评估。
