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

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.