In vitro pharmacological characterization of (±)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a nicotinic acetylcholine receptor ligand

• Published in: Brain research Vol. 981; no. 1; pp. 85 - 98
• Main Authors: Rao, Tadimeti S., Adams, Pamala B., Correa, Lucia D., Santori, Emily M., Sacaan, Aida I., Reid, Richard T., Suto, Carla M., Michel Vernier, Jean
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 15.08.2003; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Attention - drug effects; Biological and medical sciences; Brain - anatomy & histology; Brain - metabolism; Calcium - metabolism; Cell Line - metabolism; Cholinergic system; Cholinesterase Inhibitors; Cholinesterases - blood; Cognition - drug effects; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Extracellular Space - metabolism; Humans; In Vitro Techniques; Ligands; Male; Medical sciences; N-Methylaspartate - pharmacology; Neuropharmacology; Neurotransmitter Agents - metabolism; Neurotransmitters. Neurotransmission. Receptors; Nicotinic acetylcholine receptor; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacokinetics; Nomifensine - pharmacology; Pharmacology. Drug treatments; Phenols - pharmacology; Physostigmine - pharmacology; Protein Subunits - metabolism; Pyrrolidines - pharmacology; Radioligand Assay - methods; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Recombinant Proteins - metabolism; SIB-1553A; SIB-1553A; Neurotransmitters, modulators, transporters and receptors; Nicotinic acetylcholine receptor; Characterization; Cholinergic receptor; Ligand; Nicotinic receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(03)02979-2

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 α7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H 3) and serotonergic (5-HT 1 and 5-HT 2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1–5 μM), in contrast to nicotine, showed a greater selectivity for β4-subunit containing recombinant hnAChRs (α2β4, α3β4 and α4β4) vs. β2-subunit containing nAChRs (α4β2 and α3β2) both in terms of efficacy and potency. While NIC (10–30 μM) and epibatidine (0.01–0.1 μM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 μM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (≤30 μM) 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-β-erythroidine (DHβE). 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.