Fraundorfer P F, Lezama E J, Salazar-Bookaman M M, Fertel R H, Miller D D, Feller D R
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210-1291.
Chirality. 1994;6(2):76-85. doi: 10.1002/chir.530060207.
Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline , TMQ] exists as two enantiomers, and the (-)-(S)-isomer is a potent beta-adrenergic receptor (beta-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)-and (R)-enantiomers of TMQ for interaction with beta-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer > > (R)-isomer] for stimulation of beta 1- and beta 2-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were stereoselective for the (-)-(S)-isomer in membranes of guinea pig left ventricle (beta 1) and lung (beta 2) giving IARs of 115 and 389, respectively; and in E. coli expressing human beta 1- and beta 2-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta 2-AR and rat beta 3-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each beta-AR subtype, that the isomers generally fail to differentiate between the beta-AR subtypes, and that, based upon differences in IAR within beta 3-AR containing systems, subtypes of atypical beta (or beta 3)-AR may exist in adipose tissue and smooth muscle.
曲美托喹啉[1-(3',4',5'-三甲氧基苄基)-6,7-二羟基-1,2,3,4-四氢异喹啉，TMQ]以两种对映体形式存在，(-)-(S)-异构体是一种强效的β-肾上腺素能受体（β-AR）激动剂。进行实验以研究TMQ的(S)-和(R)-对映体在组织、膜组分和细胞系统中与β-AR亚型相互作用的功能和生化效力。TMQ异构体[(S)-异构体>> (R)-异构体]对豚鼠右心房和气管的β1-和β2-AR刺激的异构体活性比（IARs）分别为224和1585；这些IARs与在大鼠远端结肠（575）、大鼠棕色脂肪细胞（398）的非典型β-AR系统上观察到的相似，但在吲哚洛尔存在下与大鼠食管平滑肌（2884）的不同。在不存在吲哚洛尔的情况下，TMQ对映体的效力略有增加；然而，在大鼠远端结肠、大鼠棕色脂肪细胞和大鼠食管平滑肌中IARs保持不变。同样，放射性配体结合研究表明，TMQ异构体对β-AR的亲和力在豚鼠左心室（β1）和肺（β2）膜中对(-)-(S)-异构体具有立体选择性，IARs分别为115和389；在表达人β1-和β2-AR的大肠杆菌中IARs分别为661和724。在表达人β2-AR和大鼠β3-AR的中国仓鼠卵巢细胞中，受体亲和力和cAMP积累刺激的相应IARs分别为331和282，以及118和4678。这些结果表明，TMQ的(-)-(S)-异构体表现出高亲和力，并且是每种β-AR亚型的强效且高度立体选择性激动剂，异构体通常无法区分β-AR亚型，并且基于含β3-AR系统中IARs的差异，非典型β（或β3）-AR亚型可能存在于脂肪组织和平滑肌中。
