Design and synthesis of propranolol analogues as serotonergic agents.
Design and synthesis of propranolol analogues as serotonergic agents.
复制标题
作为血清素剂的普萘洛尔类似物的设计和合成。
DOI：
10.1021/jm00124a021
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发表时间：
1989
影响因子：
7.3
通讯作者：
Glennon,RA
中科院分区：
文献类型：
--
作者：
Pierson,ME;Lyon,RA;Titeler,M;Schulman,SB;Kowalski,P;Glennon,RA
5-羟色胺（5-HT）在不同的中心5-HT结合位点以几乎相同的亲和力结合。很少有试剂选择性结合5-HT 1A位点。β-肾上腺素能拮抗剂普萘洛尔在5-HT 1A和5-HT 1B位点上立体选择性结合（对后者具有几倍的选择性），虽然它是5-HT 1A拮抗剂，但似乎是5-HT 1B激动剂。因此，它可以作为开发新的5-HT 1A和5-HT 1B药物的先导化合物。本研究的目的是以这样的方式修改普萘洛尔的结构，以降低其对5-HT 1B和β-肾上腺素能位点的亲和力，同时保留其对5-HT 1A位点的亲和力。普萘洛尔的侧链羟基基团的去除，以及其仲胺转化为叔胺，降低了对5-HT β和β-肾上腺素能位点的亲和力。此外，将侧链缩短一个碳原子导致化合物对海马5-HT 1A位点的亲和力与外消旋普萘洛尔相当，但对5-HT 1B位点的亲和力低30至500倍，对β-肾上腺素能位点的亲和力低1000倍以上。这些初步研究的结果证明了这种方法在开发新的羟色胺能药物方面的实用性。这主要是由于发现了几个中心5-HT结合位点（即5-HT 1、5-HT 2、5-HT 3位点），并认识到这些位点可能负责控制5-HT的各种生理功能。在中心5-HT结合位点的各种群体中，5-HT 1A位点可能是研究得最好的，并且产生了最大的兴趣。1· 2已经提出5-HTu受体可能参与例如体温调节、性活动、食欲控制，以及最近一类新型抗焦虑药（即第二代芳基哌嗪抗焦虑药）的作用机制。1-3
Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The ß-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-HT1A antagonist, it appears to be a 5-HT1B agonist. As such, it could serve as a lead compound for the development of new 5-HT1A and 5-HT1B agents. The purpose of the present study was to modify the structure of propranolol in such a manner so as to reduce its affinity for 5-HT1B and/3-adrenergic sites while, at the same time, retaining its affinity for 5-HT1A sites. Removal of the side-chain hydroxyl group of propranolol, and conversion of its secondary amine to a tertiary amine, reduced affinity for 5-HT^ and/S-adrenergic sites. In addition, shortening the side chain by one carbon atom resulted in compounds with affinity for hippocampal 5-HT1A sites comparable to that of racemic propranolol, but with a 30-to 500-fold lower affinity for 5-HT1B sites and a greater than 1000-fold lower affinity for/3-adrenergic sites. The results of these preliminary studies attest to the utility of thisapproach for the development of novel serotonergic agents.The last several years have seen a growing interest in the neurotransmitter serotonin (5-HT); this is primarily due tothe identification of several central 5-HT binding sites (ie, 5-HTj, 5-HT2, 5-HT3 sites) and the realization that these sites may be responsible for controlling various physiological functions of 5-HT. Of the various populations of central 5-HT binding sites, the 5-HT1A sites have perhaps been the best studied and have generated the most interest. 1· 2 It has been proposed that 5-HTu receptors may be involved in, for example, temperature regulation, sexual activity, appetite control, and, most recently, the mecha-nism of action of a new class of anxiolytic agents (ie, second-generation arylpiperazine anxiolytics). 1-3