Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: Effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice

Holladay, Mark W.; Bai, Hao; Li, Yihong; Lin, Nan‐Horng; Daanen, Jerome F.; Ryther, Keith B.; Wasicak, James T.; Kincaid, John; He, Yun; Hettinger, Anne-Marie; Huang, Peggy; Anderson, David J.; Bannon, Anthony W.; Buckley, Michael; Campbell, John R.; Donnelly‐Roberts, Diana L.; Gunther, Karen L.; Kim, David J.B.; Kuntzweiler, Theresa A.; Sullivan, James P.; Decker, Michael; Arnerić, Stephen P.

doi:10.1016/s0960-894x(98)00504-6

Cited by 52 publications

(35 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Within this general objective, our first efforts were devoted to the synthesis of the two unreported regioisomeric 2,3-dihydro-1,4- For the preparation of the 3-substituted-2,3-dihydro-1,4-dioxin[2,3-c]pyridine 82 (Scheme 14), the MOM protected 4-chloro-3-hydroxypyridine 87 was used as starting material, prepared according to a previously described procedure [71]. The introduction of the allyloxy group by aromatic nucleophilic substitution was carried out by reaction of 87 with allyl alcohol in 1,2-dimethoxyethane (DME) using NaH as base yielding intermediate 88 [72].…”

Section: 4-benzodioxino[23-b]pyridinesmentioning

confidence: 99%

Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

Cruz‐López¹,

Núñez²,

Conejo‐García³

et al. 2011

COC

View full text Add to dashboard Cite

The 2,3-dihydro-1,4-benzodioxin ring system is present in a large number of structures of therapeutic agents possessing important biological activities. Some of them are antihypertensive agents. Others are involved in nervous breakdown and schizophrenia or represent an attractive therapeutic target for the treatment of glaucoma. The 2,3-dihydro-1,4-benzodioxin core has also been developed for the synthesis of inhibitors of 5-lipoxygenase and accordingly, these 2,3-dihydro-1,4-benzodioxins are useful for the treatment of inflammatory diseases such as asthma and arthritis. The synthesis and reactivity of several bioisosteres of the non-aromatic ring will be discussed. The occurrence of the 2,3-dihydro-1,4-benzodioxin structure in various naturally abundant compounds is also known. The total synthesis of angustureine (a novel 1,2,3,4-tetrahydroquinoline alkaloid with a n-pentyl side chain at position 2) will be presented. The bioisosteric replacement of benzene by pyridine in compounds containing the 2-substituted-2,3-dihydro-1,4-benzodioxin core has yielded derivatives of biological interest in diverse therapeutic areas such as central nervous system and cardiovascular diseases. These promising results have prompted interest in the area of 1,4-dioxino-[2,3-b]pyridine analogues. Several modifications on both the aromatic and the non-aromatic rings will be reviewed, including several transformations of the new heterocycles, such as the Smiles rearrangement. Moreover, the enantiomers of 2-and 3-hydroxymethyl-2,3-dihydro-1,4-dioxino-[2,3-b]pyridines, important chiral building blocks for the preparation of several biologically active compounds, have been synthesized. We have made an attempt to take into account the largest possible number of original papers, including our research and others. Publications of the last eleven years are included in this review.

show abstract

Section: 4-benzodioxino[23-b]pyridinesmentioning

confidence: 99%

Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

Cruz‐López¹,

Núñez²,

Conejo‐García³

et al. 2011

COC

View full text Add to dashboard Cite

show abstract

“…One azetidine, the R-enantiomer ABT-594, has been extensively studied and subjected to clinical trials as a relatively nontoxic potent analgetic (Holladay et al, 1998a,b). Substitution of the azetidine ring with methyl as in XXX reduced affinity markedly (Holladay et al, 1998a). There have been reported a few nicotinic agonists, such as chromoproline (Efange et al, 2001), SIB 1553 (Vernier et al, 1999), and XXXI (Elliott et al, 1996), that have an electron-rich phenyl moiety in place of the pyridyl ring.…”

Section: Pyridyl Ethersmentioning

confidence: 99%

“…The effect of pyridyl ring substituents on affinity of α 4 β 2 receptors has been extensively studied in particular for nicotine (Dukat et al, , 2002aSaji et al, 1997;Lee et al, 2002), open-chain analogs , certain pyridyl ethers (Holladay et al, 1998a;Lin et al, 2001;Lee et al, 2002) and epibatidine Carroll et al, 2001aCarroll et al, , 2001bCarroll et al, , 2002Avalos et al, 2002). The effects of substituents at the 5-and 6 position of the pyridyl ring on six series of nicotine analogs are tabulated in Fig.…”

Section: Substituents On the Pyridyl Ringmentioning

confidence: 99%

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

2005

View full text Add to dashboard Cite

1. Acetylcholine receptors were initially defined as nicotinic or muscarinic, based on selective activation by two natural products, nicotine and muscarine. Several further nicotinic agonists have been discovered from natural sources, including cytisine, anatoxin, ferruginine, anabaseine, epibatidine, and epiquinamide. These have provided lead structures for the design of a wide range of synthetic agents. 2. Natural sources have also provided competitive nicotinic antagonists, such as the Erythrina alkaloids, the tubocurarines, and methyllycaconitine. Noncompetitive antagonists, such as the histrionicotoxins, various izidines, decahydroquinolines, spiropyrrolizidine oximes, pseudophrynamines, ibogaine, strychnine, cocaine, and sparteine have come from natural sources. Finally, galanthamine, codeine, and ivermectin represent positive modulators of nicotinic function, derived from natural sources. 3. Clearly, research on acetylcholine receptors and functions has been dependent on key natural products and the synthetic agents that they inspired.

show abstract

“…One hundred and fifty-eight diverse pyridyl ether analogues were taken from several published works [10][11][12][13][38][39][40][41][42][43][44]. Our study was based on two fundamental Fig.…”

Section: Data Setmentioning

confidence: 99%

QSAR study of a large set of 3-pyridyl ethers as ligands of the α4β2 nicotinic acetylcholine receptor

Zhang

2007

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: Effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice

Cited by 52 publications

References 9 publications

Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

QSAR study of a large set of 3-pyridyl ethers as ligands of the α4β2 nicotinic acetylcholine receptor

Contact Info

Product

Resources

About