Summary:
In the context of the present PhD thesis, new Ν-
alkanoyl-10-x-5,6-dihydroindolo[2,1-α]isoquinolin-12-ethanamines, Ν-
alkanoyl-2-x-5-methyl-7Η-pyrrolo[3,2,1-de]phenanthridin-4-ethanamines and Ν-
alkanoyl-y-x-6,11-dihydroindolo[1,2-b]isoquinolin-11-ethanamines, were
synthesized and screened for melatoninergic action.
In detail, the 10-fluoro-substituted derivatives of general type A were
synthesized, along with their a-methyl side chain substituted congeners B.
Moreover, a series of N1-C7 (indole ring mumbering) annulated tetracyclic
compounds (Γ, Δ and E) was prepared, in order to probe the influence of this
type of annulation, compared to N1-C2 (compounds A and B), on melatoninergic
activity. Molecules Γ and Δ, which bear an α- and β-Me group, respectively to
the amide functionality of their side chains, were synthesized in an attempt to
investigate whether conformational constrain affects potency. The 3rd series of
compounds prepared belongs to the chemical class of
6,11-dihydroinolo[1,2-b]isoquinolines (ΣΤ, Ζ and Η). In this series the N1-C2
annulation, present in molecules A and B, is retained, but in this case is
1,2-b instead of 2,1-a. Moreover, the side case is translocated from C-12
(compounds A) to C-11 (1,2-b annulated ring numbering). This side chain
movement creates an asymmetric center
The melatoninergic activity of all new molecules, prepared in the context of
this PhD thesis, was investigated by employing the Xenopus laevis melanophore
assay. The reference compound for establishing agonist action was melatonin,
whilst the antagonist activity was compared to that of luzindole. Binding
studies, employing ratMT1 and ratMT2 receptors, were conducted for the most
active melatoninergics.
Compounds of general type A and B appear as melatonin receptor antagonists,
with a noteworthy potency in some cases. Conversely, their congeners Γ1(i) and
Γ1(ii) are partial agonists, with the exception of the butyramido-analogue
Γ1(iii), which is an antagonist. Compound Γ1(i) shows a two-fold selectivity
for the ratMT2 receptor compared to ratMT1. Irrespectively of the nature of the
C2-substituent, all Δ-molecules are antagonists. A two-fold selectivity for the
ratMT2 receptor is observed only for analogue Δ 1(i). The movement of the Me
side chain substituent from position a (compounds Δ) to β (compounds E) does
not alter the antagonistic activity neither to agonistic or partial agonistic.
It is, however, of particular interest the fact that propanamide E1(ii) is 76
times more selective for the ratMT2 receptor. The C-2 methoxylated compounds of
general type ΣΤ are all antagonists and so are their C1-methoxylated congeners
Z, but much more potent. Analogue Z(ii) is 1.8x more active than luzindole.
Last, the C-2,3-bismethoxylated compounds H are in general potent antagonists.
Analogue H(ii), however, is melatonin receptor partial agonist and 6-fold more
selective for the ratMT2 receptor.
Keywords:
Ν-alkanoyl-10-x-5, 6-dihydroindolo[2, 1-α]isoquinolin-12-ethanamines, Ν-alkanoyl-2-x-5-methyl-7Η-pyrrolo[3, 2, 1-de]phenanthridin-4-ethanamines, Ν-alkanoyl-y-x-6, 11-dihydroindolo[1, 2-b]isoquinolin-11-ethanamines, Melatoninergic action
