Design, synthesis and melatoninergic potency of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines.

Abstract:

:A series of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. Compounds with a single methylene spacer in the side chain (7) have no agonist activity, but are weak antagonists in the Xenopus melanophore assay, irrespectively of the size or shape of the R substituent (R=CH(3) to c-C(4)H(7)). In contrast, compounds with two (8) or three (9) methylene spacers show partial agonist activity, though this does vary with the nature of the R substituent. Interestingly, the cyclopropane and cyclobutane R substituents, which are usually linked with antagonism, render the cyclopropanecarboxamido analog 9d and its cyclobutanecarboxamido congener 9e weak agonists. It seems, therefore, that in these compounds the R substituent constitutes a functional probe in the dynamic agonist-antagonist conformational equilibrium. One of the new molecules, antagonist 8c, exhibits a noteworthy MT(2) subtype selectivity (13-fold), whereas the acetamido analog 9a (with a three methylene units spacer) also acts as an antagonist and is the only analog exhibiting MT(1) selectivity (>10-fold). In contrast to the analogous N1-C7 annulated indole derivatives, recently reported, the new C1-C8 condensed isoquinolines are not all pure antagonists. Despite their modest receptor affinity at the binding site these compounds demonstrate that the nature of the response (agonist or antagonist activity) is dependent, in this case, on both the side chain spacer's length and the size and shape of the R group.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Tsotinis A,Eleutheriades A,Hough KA,Davidson K,Sugden D

doi

10.1016/j.bioorg.2006.11.006

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

189-204

issue

2

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(06)00102-7

journal_volume

35

pub_type

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