title: In vivo pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol hydrochloride (SIB-1553A), a novel cholinergic ligand: microdialysis studies.
abstract: SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.
authors.affiliation: Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. tadimeti_rao@merck.com
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Richard T
authors.initials: RT
authors.lastname: Reid
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Correa
authors.forename: Emily M
authors.initials: EM
authors.lastname: Santori
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Aida I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: Daniel
authors.initials: D
authors.lastname: Lorrain
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vernier
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D004333:Drug Administration Routes; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000097:blood / Q000493:pharmacokinetics*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010636:Phenols / Q000097:blood / Q000493:pharmacokinetics*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010636:Phenols; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D011978:Receptors, Nicotinic; D000109:Acetylcholine; D004298:Dopamine