David S. Garvey

A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: In Vitro pharmacological properties of a novel, high affinity α4β2 nicotinic acetylcholine receptor ligand

Abstract The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2( S )-azetidinylmethoxy) pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human α4β2 nAChR subtype ( K i = 0.05 ± 0.01 nM) relative to the human α7 ( K i = 148 ± 13 nM) and the muscle α1β1dg subtype expressed in Torpedo electroplax ( K i = 314 ± 12 nM). The R -enantiomer of A-85380, A-159470, displays little enantioselectivity towards the α4β2 and α1β1δγ subtypes but does display 12-fold enantioselectivity towards the α7 subtype ( K i = 1275 ± 199 nM). (+)- and (−)-Epibatidine display similar potencies at the human human α4β2 ( K i = 0.04 ± 0.02 nM and 0.07 ± 0.02 nM, respectively), human α7 ( K i = 16 ± 2 nM and 22 ± 3 nM, respectively) and muscle α1β1δg ( K i = 2.5 ± 0.9 nM and 5.7 ± 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human α4β2 (EC 50 = 0.7 ± 0.1 μ M) and ganglionic (EC 50 = 0.8 ± 0.09 μ M) subtypes, effects that are attenuated by pretreatment with mecamylamine (10 μM). Further, A-85380 can activate (EC 50 = 8.9 ± 1.9 μ M) currents through channels formed by injection of the human α7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the α7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (−)-nicotine but less potent than (±)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine with an EC 50 value of 0.003 ± 0.001 μ M which is equipotent to (±)-epibatidine, and 20-fold more potent that (−)-nicotine (EC 50 = 0.04 ± 0.009 μ M). Thus, A-85380 displays a profile of robust activation of a number of nAChR subtypes with substantially less affinity for [ 125 I]α-BgT sites than [ 3 H](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the αx4β2 subtype relative to the α7 and α1β1δg nAChRs than (±)-epibatidine.

2-(Aryloxymethyl) azacyclic analogues as novel nicotinic acetylcholine receptor (nAChR) ligands

Abstract A series of 2-(aryloxymethyl) azetidine and pyrrolidine nAChR ligands in which the 3-pyridyl moiety of a previously described series 1 was replaced by a substituted phenyl group was explored. Aromatic substitution afforded analogues with K i values ranging from 3 to >10,000 nM. Generally, substitution at the ortho - and para -position was unfavorable, whereas electron-withdrawing groups at the meta -position improved the K i values.

Phenyl pyrrolidine analogues as potent nicotinic acetylcholine receptor (nAChR) ligands

Abstract The synthesis and SAR of a series of 2-phenyl pyrrolidines as neuronal nAChR ligands are described. Substitution on the aryl ring had a dramatic effect on receptor binding affinity, with Ki values ranging from 46 nM to >10,000 nM. Analogues 8, 9, and 14 were the most potent ligands evaluated, having Ki values of 68 nM, 75 nM, and 46 nM; respectively.

Structure-activity studies on a novel series of cholinergic channel activators based on a heteroaryl ether framework.

Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).

ABT-418: A Novel Cholinergic Channel Activator (ChCA) for the Potential Treatment of Alzheimer’s Disease

Evidence is accumulating to suggest that compounds which activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer’s disease (AD) (for review: Arneric and Williams, 1994). The focus of this chapter is to summarize the preclinical pharmacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole], a novel analog of (-)-nicotine that is in clinical development for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine (Americ et al., 1994; Decker et al., 1994a). The enhanced preclinical safety profile and excellent transdermal delivery across species are consistent with the early Phase I clinical studies (Sebree et al., 1993).

Cyclopentanedi- and tricarboxylic acids as squalene synthase inhibitors: Syntheses and evaluation

Based on earlier lead squalene synthase inhibitor A-87049 (3) and zaragozic acids, a series of cyclopentanedi- and tricarboxylic acids were synthesized and evaluated against the enzyme. Some exhibited good potency and SAR revealed the importance of conformation and substitution pattern of these synthetic inhibitors.