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Titolo:
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 '-substituted 5 '-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine analogues
Autore:
Carroll, FI; Liang, F; Navarro, HA; Brieaddy, LE; Abraham, P; Damaj, MI; Martin, BR;
Indirizzi:
Res Triangle Inst, Res Triangle Pk, NC 27709 USA Res Triangle Inst Res Triangle Pk NC USA 27709 Triangle Pk, NC 27709 USA Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA Virginia Commonwealth Univ Richmond VA USA 23298 , Richmond, VA 23298 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 13, volume: 44, anno: 2001,
pagine: 2229 - 2237
SICI:
0022-2623(20010621)44:13<2229:SNARBA>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHOLINERGIC RECEPTORS; HIGH-AFFINITY; HUMAN BRAIN; DERIVATIVES; LIGANDS; TARGETS; PET; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Carroll, FI Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA Res Triangle Inst POB 12194 Res Triangle Pk NC USA 27709 9 USA
Citazione:
F.I. Carroll et al., "Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 '-substituted 5 '-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine analogues", J MED CHEM, 44(13), 2001, pp. 2229-2237

Abstract

A convenient, high-yield synthesis of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (5), which involved the addition of tributyltin hydride to 7-tert-butoxycarbonyl-2-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-ene (4)followed by elimination of the tributyltin and p-tolylsulfonyl groups using tetrabutylammonium fluoride was developed. The addition of 2-amino-5-iodopyridine to 5 under reductive. Heck conditions provided 7-tert-butoxycarbonyl-2-exo-(2 ' -amino-5 ' -pyridinyl)-7-azabicyclo [2.2.1]heptane (6). Compound 6 was the key intermediate used to prepare epibatidine analogues where the 2 ' -chloro group on the pyridine ring was replaced with a fluorine (Ib), bromine (1c), iodine (1d), hydroxy (1e), amino (1f), dimethylamino (1g),trifluoromethanesulfonate (1h), and hydrogen (1i) group. (+)- and (-)-Epibatidine and compounds 1b-d and Ii all possess similar binding affinities atthe alpha (4)beta (2) nAChR receptors labeled by [H-3]epibatidine. Compound If has affinity similar to nicotine, whereas compounds le, Ig, and Ih have much lower affinity. The binding affinity appears to be dependent upon the electronic nature of the substituent. However, other factors are also involved. None of the compounds possesses appreciable affinity for the alpha (7) nAChR labeled by [I-125]iodo-MLA. With the exception of If and Ig, all the epibatidine analogues are full agonists (tail flick test) in producing antinociception after intrathecal injection in mice.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/09/20 alle ore 16:12:24