(Z)-2-(3-Hydroxy-4-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one

Abstract

Crystals of the title compound, C 15 H 17 NO 3 , were obtained from a condensation reaction of 3-hydroxy-4-methoxybenzaldehyde with 1-azabicyclo[2.2.2]octan-3-one and subsequent crystallization of the product from methanol. The title compound, containing a double bond that connects the azabicyclic ring system to the 3-hydroxy-4-methoxybenzylidene group, was obtained with Z geometry. CommentDopamine is a biogenic amine biosynthesized in the hypothalamus, the arcuate nucleus, the caudad, and various areas of the central and peripheral nervous system. It has been widely established that dopamine and dopamine analogues play an important role in cardiovascular, renal, hormonal and central nervous system regulation through stimulation of and adrenergic and dopaminergic receptors.Dopamine receptor agonists and antagonists have been evaluated and extensively reviewed as medications for cocaine abuse (Witkin, 1994;Mello & Negus, 1996). Although the behavioural effects of cocaine are not consistently altered by selective dopamine receptor antagonists (Spealman, 1990;Witkin et al., 1991), many studies have reported their mediation of the reinforcing effects of cocaine (Corrigall & Coen, 1991;Britton et al., 1991).The dopamine D 3 receptor has been of particular interest, because of its relatively restricted localization within the limbic system compared with the dopamine D 2 receptor, and due to its role as a possible target for the treatment of schizophrenia and drug abuse (Shafer & Levant, 1998). A recent report of selective inhibition of cocaine-seeking behaviour by a partial dopamine D 3 receptor agonist suggested that this receptor is an important target for the development of medications for cocaine abuse (Pilla et al., 1999).The nicotinic modulation of [ 3 H]dopamine release from striatal preparations has been exploited as a model system for examining native nicotine acetylcholine receptor (nAChR) responses (Soliakov & Wonnacott, 1996;Grady et al., 1997) and evaluating novel ligands (Holladay et al., 1997;Bencherif et al., 1998;Xu et al., 2002). 1-Azabicyclo[2.2.2]octane is a very important biological moiety, and its analogues are agonists at the 7 nAChR subtype, with selective af®nity for the 7 versus 4 2 nAChR subtype (Mullen et al., 2000). In view of these ®ndings, we planned to synthesize rigid analogues of dopamine. The title compound, (I), is a synthetic precursor of a drug candidate designed as a conformationally restrained dopamine analogue with de®ned double-bond geometry, and was prepared by condensation of 3-hydroxy-4-methoxybenzaldehyde with 1-azabicyclo[2.2.2]octan-3-one under base catalysis to afford a single geometrical isomer. The product, (Z)-2-(3-hydroxy-4-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one, (I), was identi®ed by NMR spectroscopy. In order to con®rm the geometry of this compound, and to obtain more detailed information on the structural conformation of the molecule and on synthetic products derived from this intermediate that may be of value in subsequent structure±activity studies,...

Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms

“…The Williamson method was initially used to couple hydroxyl benzaldehydes (1-4) and alkyl bromides to produce the corresponding alkyloxy benzaldehydes (5a-k). The 5a-k compounds were subsequently coupled with 3-quinuclidinone, producing the ␣,␤-unsaturated ketones (6a-k) (Vijayakumar et al, 2003(Vijayakumar et al, , 2005. The C C double bond was hydrogenated using palladium/charcoal as catalyst, and a modified Wolff-Kishner strategy (Scheiber and Nemes, 2008) was used to reduce the carbonyl group to furnish the desired compounds (7a-7k).…”