Karla R, Ebert B, Thorkildsen C, Herdeis C, Johansen T N, Nielsen B, Krogsgaard-Larsen P
NeuroScience PharmaBiotec Research Centre, Department of Pharmacology The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. Lebensmittelchemie.
J Med Chem. 1999 Jun 3;42(11):2053-9. doi: 10.1021/jm990076+.
(RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acidB (GABAB) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R, 5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12. HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABAA or GABAB receptor sites and was inactive as an agonist or an antagonist at GABAB receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABAA receptor sites, and in agreement with the findings for (S)-baclofen, 12 did not interact significantly with GABAB receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 microM), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 microM) as an inhibitor of GABAB binding. Accordingly, 11 (EC50 = 150 +/- 23 microM) was shown to be weaker than 2 (EC50 = 11 +/- 1 microM) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABAB antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 microM) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.
合成了（RS）-5-氨基-4-（4-氯苯基）戊酸（10）以及（RS）-5-氨基-3-（4-氯苯基）戊酸的R型（11）和S型（12），它们是4-氨基丁酸B（GABAB）受体激动剂（RS）-4-氨基-3-（4-氯苯基）丁酸（巴氯芬）的同系物。化合物10通过使用七步反应序列在巴氯芬的羧基末端进行同系化反应合成。N-叔丁氧羰基保护的（4R，5R）-4-（4-氯苯基）-5-羟基-2-哌啶酮（18）通过改良的巴顿-麦康比反应脱氧得到N-叔丁氧羰基保护的（R）-4-（4-氯苯基）-2-哌啶酮（20），其开环并脱保护得到11·HCl。相应的S-对映体12·HCl由18的4S，5S-对映体即化合物21类似地合成。通过手性高效液相色谱法测定了11·HCl（对映体纯度ee = 99.8%）和12·HCl（对映体纯度ee = 99.3%）的对映体纯度。化合物10对GABAA或GABAB受体位点未显示出可检测到的亲和力，并且在豚鼠回肠中作为GABAB受体的激动剂或拮抗剂无活性。与巴氯芬的对映体一样，11和12对GABAA受体位点均未显示出可检测到的亲和力，并且与（S）-巴氯芬的研究结果一致，12与GABAB受体位点无明显相互作用。化合物11（IC50 = 7.4±0.6微摩尔）是（R）-巴氯芬（2）的同系物，作为GABAB结合的抑制剂，其活性比2（IC50 = 0.14±0.01微摩尔）弱约50倍。因此，作为豚鼠回肠电诱导收缩的抑制剂，11（EC50 = 150±23微摩尔）比2（EC50 = 11±1微摩尔）弱。然而，虽然2的这种作用对GABAB拮抗剂CGP35348（4）敏感，但11的抑制作用未受到明显影响。此外，在该测试系统中，12（EC50 = 310±16微摩尔）的效力仅为11的一半，并且12的这种作用对4也不敏感。观察结果强调了2与化合物11和12药理作用的差异，即2仅将回肠收缩抑制59±5%，而11和12均显示出对该反应的抑制率约为94%。11和12似乎均未对回肠中的胆碱能机制产生明显影响，它们的作用机制仍然不明。
