Giri Rajan, Namballa Hari K, Sarker Ananta, Alberts Ian, Harding Wayne W
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA.
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
Bioorg Chem. 2022 Oct;127:105953. doi: 10.1016/j.bioorg.2022.105953. Epub 2022 Jun 22.
The 1-phenylbenzazepine scaffold has yielded several D1R targeting ligands, but some gaps remain in our understanding of the structure-activity relationships in this scaffold. In particular, there is a paucity of studies that have investigated the effects of substituents at the C2' position of 1-phenylbenzazepines on their affinity and selectivity towards D1R. In this study, a set of methyl- and fluoro- C2'-substituted 1-phenylbenzazepines, with ring A catechol or 8-hydroxy-7-methoxy moieties in tandem with N-methyl or N-allyl substituent groups, was synthesized and evaluated for affinity at a subset of dopamine receptors - D1R, D2R and D5R. These studies indicate that an N-methyl group is generally preferred over N-unsubstituted or N-allyl groups for strong D1R affinity. In addition, it was revealed that compounds with a ring A 8-hydroxy-7-methoxy motif displayed stronger D1R affinity than analogous compounds with a ring A catechol moiety. Furthermore, the presence of a C2' substituent does not significantly impact D1R selectivity over D5R. However, for all analogs assessed, D1R selectivity over D2R was maintained. D1R vs D5R selectivity was generally poor or modest (less than 10-fold) among members of the series. A new high affinity selective D1R ligand - 10b (K = 5.7 nM), was identified in this study; further pharmacological characterization indicates that 10b is an antagonist at D1R (IC = 10.7 nM). Docking studies on 10b indicate that a number of interactions with hydrophobic residues (Trp321, Val317, Phe313, Phe289, Phe288, Phe285, Phe203, Tyr194, Leu190, Ser188, His 164, Ile104, Val100 and Trp99) in addition to the typical N-Asp103 salt bridge are important for its D1R affinity.
1-苯基苯并氮杂卓骨架已产生了几种靶向D1R的配体，但我们对该骨架结构-活性关系的理解仍存在一些空白。特别是，很少有研究调查1-苯基苯并氮杂卓C2'位取代基对其与D1R亲和力和选择性的影响。在本研究中，合成了一组C2'位甲基和氟取代的1-苯基苯并氮杂卓，其A环带有儿茶酚或8-羟基-7-甲氧基部分，并串联有N-甲基或N-烯丙基取代基，评估了它们对多巴胺受体子集——D1R、D2R和D5R的亲和力。这些研究表明，对于强D1R亲和力，N-甲基基团通常比N-未取代或N-烯丙基基团更受青睐。此外，研究发现具有A环8-羟基-7-甲氧基基序的化合物比具有A环儿茶酚部分的类似化合物表现出更强的D1R亲和力。此外，C2'取代基的存在对D1R相对于D5R的选择性没有显著影响。然而，对于所有评估的类似物，D1R相对于D2R的选择性得以保持。该系列成员中D1R与D5R的选择性通常较差或适中（小于10倍）。在本研究中鉴定出一种新的高亲和力选择性D1R配体——10b（K = 5.7 nM）；进一步的药理学表征表明10b是D1R的拮抗剂（IC = 10.7 nM）。对10b的对接研究表明，除了典型的N-Asp103盐桥外，与疏水残基（Trp321、Val317、Phe313、Phe289、Phe288、Phe285、Phe203、Tyr194、Leu190、Ser188、His 164、Ile104、Val100和Trp99）的一些相互作用对其D1R亲和力很重要。
