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Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5‐HT 2A , Dopamine and Histamine H 1 Receptor Ligands
Author(s) -
Rostom Sherif A. F.
Publication year - 2010
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200900219
Subject(s) - chemistry , stereochemistry , indole test , pyrrole , indolizine , histamine , serotonin , 5 ht receptor , moiety , receptor , ring (chemistry) , dopamine , biochemistry , pharmacology , organic chemistry , biology , neuroscience
LE 300 represents a structurally novel type of antagonists acting preferentially at the dopamine D 1 /D 5 receptors and the serotonin 5‐HT 2A receptor. This compound consists of a ten‐membered central azecine ring fused to an indole ring on one side and a benzene moiety on the other side. To estimate the importance of the indole and / or phenyl moieties in this highly active benz‐indolo‐azecine, both rings were removed and replaced with a 1 H ‐pyrrole counterpart. Accordingly, some new analogs of LE 300 namely, pyrrolo[2,3‐ g ]indolizine, pyrrolo[3,2‐ a ]quinolizine rings and their corresponding dimethylpyrrolo[2,3‐ d ]azonine, and dimethylpyrrolo[2,3‐ d ]azecine were synthesized to be evaluated for their activity at the 5‐HT 2A and dopamine D 1 , D 2L , D 4 , D 5 receptors in relation to LE 300 . In addition, their activity at the H 1 ‐histamine receptors was also determined. The results suggested that the rigid pyrrolo[2,3‐ g ]indolizine 7 and pyrrolo[3,2‐ a ]quinolizine 8 analogs lacked biological activity in the adopted three bioassays. However, their corresponding flexible pyrrolo[2,3‐ d ]azonine 11 and pyrrolo[2,3‐ d ]azecine 12 derivatives revealed weak partial agonistic activity and weak antagonistic potency at the serotonin 5‐HT 2A and histamine H 1 receptors, respectively. Meanwhile, they showed no affinity to any of the four utilized dopamine receptors. Variation in ring size did not contribute to a significant influence on the three tested bioactivities. Removal of the hydrophobic moiety (phenyl ring) and replacement of the indole moiety with a 1 H ‐pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine‐type compounds.