69808-72-6Relevant academic research and scientific papers
Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
Mistry, Shailesh N.,Shonberg, Jeremy,Draper-Joyce, Christopher J.,Klein Herenbrink, Carmen,Michino, Mayako,Shi, Lei,Christopoulos, Arthur,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert
, p. 6819 - 6843 (2015/09/22)
Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
Synthetic studies on indoles and related compounds. XXVI. The debenzylation of protected indole nitrogen with aluminum chloride. (2)
Watanabe,Kobayashi,Nishiura,Takahashi,Usui,Kamiyama,Mochizuki,Noritake,Yokoyama,Murakami
, p. 1152 - 1156 (2007/10/02)
A new debenzylation method using aluminum chloride in benzene or anisole, which had been developed by us for N-benzyl-2-acyl- and -2-ethoxycarbonylindoles, was applied to benzyl derivatives of other types of indoles and related compounds. Among them, N-benzyl derivatives of fully aromatized indoles, carbazoles and β-carbolines, and some benzamides were debenzylated successfully, whereas those of oxindoles and heterocyclic amides were not. As to the effect of a p-substituent on the benzyl group, it was found that an electron-donating substituent accelerates deprotection, whereas an electron-attracting substituent delays or prevents deprotection.
