Defunctionalized lobeline analogues: Structure-activity of novel ligands for the vesicular monoamine transporter
Defunctionalized lobeline analogues: Structure-activity of novel ligands for the vesicular monoamine transporter
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DOI：
10.1021/jm0501228
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发表时间：
2005-08-25
影响因子：
7.3
通讯作者：
Crooks, PA
中科院分区：
文献类型：
--
作者：
Zheng, GR;Dwoskin, LP;Crooks, PA
(-)-洛贝林(2R，6S，10S；1a)是烟碱型乙酰胆碱受体(NAChRs)的拮抗剂，可抑制甲基苯丙胺的神经化学和行为效应，并抑制多巴胺转运体(DAT)和囊泡单胺转运体(VMAT2)的功能。VMAT2是开发甲基苯丙胺滥用治疗方法的目标。通过对洛贝林进行结构修饰，得到了对VMAT2具有较高活性和选择性的官能化类似物中间质二烯(MTD)和洛贝林。为了在这类新的VMAT2配体中建立构效关系，已经合成了MTD、洛贝烷和其他结构相关的类似物的特定立体化学形式。评价了这些化合物对[H-3]尼古丁([H-3]NIC)结合(α4β2*nAChR)、[H-3]甲基乌头碱([H-3]MLA)结合(α7*nAChR)和[H-3]二氢四苯并([H-3]DTBZ)结合(VMAT2)的抑制作用。一般来说，与洛贝林相比，所有这些类似物在α4β2*和α7*nAChRs上的亲和力都较低，从而提高了对VMAT2的选择性。下列结构修饰仅导致VMAT2亲和力的轻微变化，提供了比先导化合物洛贝拉烷更弱的类似物：(1)改变了哌啶环的C-2和C-6位的立体化学，(2)改变了哌啶基C-2和C-6取代基的不饱和度，(3)在哌啶环中引入了不饱和度，(4)开环或消除了哌啶环，以及(5)去除了哌啶基N-甲基。此外，在顺式系列的去功能化的洛贝林分子中加入季铵基团会导致与VMAT2的亲和力显著降低，而反式系列的亲和力仅有轻微的变化。被评价的最有效的化合物(K-I=630 nm)和对VMAT2的选择性是N-methyl-2，6-cis-bis(naphthaleneethyl)piperidine类似物28b(1-nap-lobelane)，其中lobelane的苯基被1-萘基取代。因此，初步的构效关系研究表明，导致VMAT2亲和力和选择性增强的洛贝林分子最有希望的结构变化是官能化，提供洛贝兰和MTD，以及洛贝兰的苯环被其他具有pi-扩展结构的芳香族部分取代。
(-)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure-activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. These compounds have been evaluated for inhibition of [H-3]nicotine ( [H-3]NIC) binding (alpha 4 beta 2* nAChR), [H-3]methyllycaconitine ([H-3]MLA) binding (alpha 7* nAChR), and [H-3]dihydrotetrabenazine ([H-3]DTBZ) binding (VMAT2). Generally, all of these analogues had lower affinities at alpha 4 beta 2* and alpha 7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the trans-series. The most potent (K-i = 630 nM) and VMAT2-selective compound evaluated was the N-methyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure-activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a pi-extended structure.