Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: Steric and electronic effects of 4- and 8-halogenated naphthoyl substituents
2012
Wiley, Jenny L. | Smith, Valerie J. | Tan, Kim Hong | Martin, Billy R. | Huffman, John W.
To develop SAR at both the cannabinoid CB₁ and CB₂ receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB₁ and CB₂ receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure–activity relationships are presented. Although many of these compounds are selective for the CB₂ receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB₁ affinity and good CB₂ affinity.
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