Dopamine D₃ Receptor Antagonists. 1. Synthesis and Structure−Activity Relationships of 5,6-Dimethoxy-N-alkyl- and N-Alkylaryl-Substituted 2-Aminoindans

Abstract

5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

Modulation of expression of IL-8 gene in bronchial epithelial cells by 5-methoxypsoralen

“…Indanone derivatives have been widely studied for different pharmacological applications, such as the inhibition of dopamine D3 receptor [36] with potential use in anti-psychotic therapy, of acetylcholinesterase activity for Alzheimer's disease [37,38] or even as anti-cancer molecules [39,40]. In this respect, 5,6-dimethoxy-1-indanone has been utilized as one of the basic compounds useful for further derivatization [36]. Interesting molecular modeling studies have been pursued in order to gain insights on the interactions of indanone derivatives such as 5,6-dimethoxy-2-(4-piperidinyl)methyl-1-indanone or donepezil-tacrine hybrid, with acetylcholinesterase [38].…”

Effects of dopaminergic compounds on carbonic anhydrase isozymes I, II, and VI

“…The hydrochloride salt of 4 has been reported to be useful as an analgesic 23 . 5,6-Dimethoxy-2-(N-dipropyl)-aminoindan, PNU-99194A, has been reported to be a selective dopamine D 3 receptor antagonist with potential antipsychotic properties in animal models 24 .…”

Current perspectives on the selective regulation of dopamine D2 and D3 receptors

“…Introduction of two methoxy-functions into positions 5 and 6 of the aminoindan scaffold gave the symmetrical compound, U 99194A (Waters et al, 1993;Haadsma-Svensson et al, 2001) (Fig. 3I).…”