Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists.
1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.
Elokdah
Hassan
H
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. elokdah@wyeth.com
Li
David
D
McFarlane
Geraldine
G
Bernotas
Ronald C
RC
Robichaud
Albert J
AJ
Magolda
Ronald L
RL
Zhang
Guo Ming
GM
Smith
Deborah
D
Schechter
Lee E
LE
D001667:Binding, Competitive; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor