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

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 1H-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 1H-pyrrole counterpart led to a dramatic alteration in the profile of activity of such azecine-type compounds.