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

被引：17

作者：

Rao, TS ^{[1
]}

Adams, PB ^{[1
]}

Correa, LD ^{[1
]}

Santori, EM ^{[1
]}

Sacaan, AI ^{[1
]}

Reid, RT ^{[1
]}

Suto, CM ^{[1
]}

Vernier, JM ^{[1
]}

机构：

[1] Merck Res Labs, San Diego, CA 92121 USA

来源：

BRAIN RESEARCH | 2003年 / 981卷 / 1-2期

关键词：

SIB-1553A; nicotinic acetylcholine receptor;

D O I：

10.1016/S0006-8993(03)02979-2

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

SIB-1553A ((+/-)-4-[2-(l-methyl-2-pyrrolidinyl)ethyl]thio]phenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which displaced the binding of [H-3]nicotine (NIC) to the rat brain nAChRs with an IC50 value of 110 nM with no appreciable affinity to the alpha7 nAhRs. SIB-1553A showed modest affinity for histaminergic (H-3) and serotonergic (5-HT1 and 5-HT2) receptors, and sigma binding sites. In calcium flux assays, SIB-1553A (0.1-5 muM), 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 muM) and epibatidine (0.01-0.1 muM) fully activated human muscle-type AChRs expressed by RD cell line, SIB-1553A was virtually ineffective for up to >100 muM and elicited less than 10% of the response due to suberyldicholine. SIB-1553A (less than or equal to 30 muM) evoked [H-3]DA release from striatum, olfactory tubercles and prefrontal cortex (PFC), and [H-3]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 [H-3]NE from the rat hippocampus and antagonized NIC response upon co-application implying partial agonist properties. SIB-1553A did not evoke basal [H-3]ACh release from the rat striatum or hippocampus, but attenuated NMDA-evoked [H-3]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. (C) 2003 Elsevier B.V. All rights reserved.

引用

页码：85 / 98

页数：14

共 37 条

[1] BIOCHEMICAL AND PHARMACOLOGICAL CHARACTERIZATION OF [H-3] GBR-12935 BINDING INVITRO TO RAT STRIATAL MEMBRANES - LABELING OF THE DOPAMINE UPTAKE COMPLEX [J].