Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist.
A small series of aryl pyridyl sulfones has been prepared and investigated for its 5-HT(6) receptor binding properties. Thereof, pyrrolidinyl derivative 11 proved to be a very potent (pK(i) 9) and selective 5-HT(6) receptor antagonist. By means of in vivo microdialysis in the frontal cortex and a passive avoidance paradigm, where 11 reversed a scopolamine induced retention deficit, a functional correlation between 5-HT(6) receptors and cholinergic neurotransmission could be shown, supporting the therapeutic potential of 5-HT(6) receptors in the treatment of cognitive deficits.
Riemer
Claus
C
F. Hoffmann-LaRoche, Pharma Division, Preclinical Research, CH-4070 Basel, Switzerland.
Borroni
Edilio
E
Levet-Trafit
Bernard
B
Martin
James R
JR
Poli
Sonia
S
Porter
Richard H P
RH
Bös
Michael
M
D000109:Acetylcholine / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001682:Biological Availability; D001812:Blood-Brain Barrier; D002460:Cell Line; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D017551:Microdialysis; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution
C473484:4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor; D000109:Acetylcholine