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J Med Chem ; 44(26): 4716-32, 2001 Dec 20.
Article in English | MEDLINE | ID: mdl-11741489

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.


Subject(s)
Dopamine Antagonists/chemical synthesis , Indans/chemical synthesis , Receptors, Dopamine D2/drug effects , Animals , Binding, Competitive , CHO Cells , Cell Division/drug effects , Cricetinae , Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Hepatocytes/drug effects , Hepatocytes/metabolism , In Vitro Techniques , Indans/chemistry , Indans/pharmacology , Male , Motor Activity/drug effects , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3 , Structure-Activity Relationship
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