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1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase.

Abstract：

:In order to determine the function of epinephrine (Epi) in the central nervous system, we have targeted the enzyme that catalyzes the final step in the biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). 1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzyme, but also display affinity for the alpha2-adrenoceptor. To gain further understanding about how THIQs bind at the PNMT active site and in an attempt to further increase the selectivity of THIQ-type inhibitors versus the alpha2-adrenoceptor, a series of cis- and trans-1,3-dimethyl-7-substituted-THIQs were synthesized. Evaluation of these compounds suggests that THIQs bind in two different orientations at the PNMT active site, based on the lipophilicity of the 7-substituent. However, no significant increases in selectivity versus the alpha2-adrenoceptor were observed for these compounds.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Grunewald GL,Caldwell TM,Li Q,Criscione KR

doi

10.1016/s0968-0896(99)00031-0

subject

Has Abstract

pub_date

1999-05-01 00:00:00

pages

869-80

issue

5

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(99)00031-0

journal_volume

7

pub_type

杂志文章

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