Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure-Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities toward Phenylethanolamine N-Methyltransferase and the 伪2-Adrenoceptor was written by Grunewald, Gary L.;Dahanukar, Vilas H.;Jalluri, Ravi K.;Criscione, Kevin R.. And the article was included in Journal of Medicinal Chemistry in 1999.Electric Literature of C10H11ClF3N This article mentions the following:
7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of epinephrine. Unfortunately, most of these compounds also exhibit strong affinity for the 伪2-adrenoceptor. To design a selective (PNMT vs 伪2-adrenoceptor affinity) inhibitor of PNMT, the steric and electrostatic factors responsible for PNMT inhibitory activity and 伪2-adrenoceptor affinity were investigated by evaluating a number of 7-substituted-THIQs. A classical quant. structure-activity relationship (QSAR) study resulted in a three-parameter equation for PNMT (PNMT pKi = 0.599蟺 – 0.0725MR + 1.55蟽m + 5.80; n = 27, r = 0.885, s = 0.573) and a three-parameter equation for the 伪2-adrenoceptor (伪2 pKi = 0.599蟺 – 0.0542MR – 0.951蟽m + 6.45; n = 27, r = 0.917, s = 0.397). These equations indicated that steric effects and lipophilicity play a similar role at either active site but that electronic effects play opposite roles at either active site. Two binding orientations for the THIQs were postulated such that lipophilic and hydrophilic 7-substituents would not occupy the same region of space at either binding site. Using these two binding orientations, based on the lipophilicity of the 7-substituent, comparative mol. field anal. (CoMFA) models were developed that showed that the steric and electrostatic interactions at both sites were similar to those previously elaborated in the QSAR analyses. Both the QSAR and the CoMFA analyses showed that the steric interactions are similar at the PNMT active site and at the 伪2-adrenoceptor and that the electrostatic interactions were different at the two sites. This difference in electrostatic interactions might be responsible for the selectivity of THIQs bearing a nonlipophilic electron-withdrawing group at the 7-position. These QSAR and CoMFA results will be useful in the design of potent and selective (PNMT vs 伪2-adrenoceptor affinity) inhibitors of PNMT. In the experiment, the researchers used many compounds, for example, 7-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (cas: 220247-87-0Electric Literature of C10H11ClF3N).
7-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (cas: 220247-87-0) belongs to tetrahydroisoquinoline derivatives. Tetrahydroisoquinoline, as a secondary amine, tetrahydroisoquinoline has weakly basic properties and forms salts with strong acids. Because of the high biological relevance of compounds possessing the 1,2,3,4-tetrahydroisoquinoline framework, a large number of synthetic approaches towards the creation of an isoquinoline or 1,2,3,4-tetrahydroisoquinoline core are presently known. However, synthetic routes to tetrahydroisoquinoline derivatives containing fluorine atom(s) in their structure are not particularly abundant.Electric Literature of C10H11ClF3N
Referemce:
Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem