title: In vitro pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a nicotinic acetylcholine receptor ligand.
abstract: SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which displaced the binding of [3H]nicotine (NIC) to the rat brain nAChRs with an IC(50) value of 110 nM with no appreciable affinity to the alpha7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H3) and serotonergic (5-HT1 and 5-HT2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1-5 microM), in contrast to nicotine, showed a greater selectivity for beta4-subunit containing recombinant hnAChRs (alpha2beta4, alpha3beta4 and alpha4beta4) vs. beta2-subunit containing nAChRs (alpha4beta2 and alpha3beta2) both in terms of efficacy and potency. While NIC (10-30 microM) and epibatidine (0.01-0.1 microM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 microM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (< or =30 microM) evoked [3H]DA release from striatum, olfactory tubercles and prefrontal cortex (PFC), and [3H]NE release from hippocampus and PFC, and this evoked release was sensitive to mecamylamine (MEC). SIB-1553A-evoked neurotransmitter release exhibited region- and transmitter-specific antagonism by dehydro-beta-erythroidine (DHbetaE). SIB-1553A was less efficacious than NIC at evoking [3H]NE from the rat hippocampus and antagonized NIC response upon co-application implying partial agonist properties. SIB-1553A did not evoke basal [3H]ACh release from the rat striatum or hippocampus, but attenuated NMDA-evoked [3H]ACh release from the rat striatum. SIB-1553A did not inhibit rat brain cholinesterase for up to 1 mM. Multiple receptor affinities and release of several neurotransmitters may underlie the cognitive-enhancing effects of SIB-1553A documented in rodent and primate models.
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: Pamala B
authors.initials: PB
authors.lastname: Adams
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Correa
authors.forename: Emily M
authors.initials: EM
authors.lastname: Santori
authors.forename: Aida I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: Richard T
authors.initials: RT
authors.lastname: Reid
authors.forename: Carla M
authors.initials: CM
authors.lastname: Suto
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Vernier
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line / Q000378:metabolism; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases / Q000097:blood; D003071:Cognition / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics; D009627:Nomifensine / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D002800:Cholinesterase Inhibitors; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010636:Phenols; D021122:Protein Subunits; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D009627:Nomifensine; D016202:N-Methylaspartate; D010830:Physostigmine; D002802:Cholinesterases; D002118:Calcium