Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2- exo -2-(2‘-Substituted 5‘-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine Analogues
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 (1b), bromine (1c), iodine (1d), hydroxy (1e), amino (1f), dimethylamino (1g), trifluoromethanesulfonate (1h), and hydrogen (1i) group. (+)- and (-)-Epibatidine and compounds 1b-d and 1i all possess similar binding affinities at the alpha(4)beta(2) nAChR receptors labeled by [(3)H]epibatidine. Compound 1f has affinity similar to nicotine, whereas compounds 1e, 1g, and 1h 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 [(125)I]iodo-MLA. With the exception of 1f and 1g, all the epibatidine analogues are full agonists (tail flick test) in producing antinociception after intrathecal injection in mice.
[Show abstract] [Hide abstract] ABSTRACT: Neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane ligand-gated ion channels. Recent research demonstrated that selective nAChR ligands may have therapeutic potential in a number of CNS diseases and disorders. The alkaloid epibatidine is a highly potent non-opioid analgesic and nAChR agonist, but too toxic to be a useful ligand. To develop ligands selective for distinct nAChR subtypes and with reduced toxicity, a series of epibatidine and homoepibatidine analogues were synthesized. (+/-)-8-Methyl-3-(pyridin-3-yl)-8-azabicyclo[3,2,1]oct-2-ene, showed high affinity towards alpha4beta2 (Ki=2 nM), subtype selectivity (alpha4beta2/alpha7 affinity ratio>100) and relatively low toxicity in mice and can be labeled with 11C and 18F as positron emission tomography (PET) tracers for imaging of nAChRs.0Comments 10Citations
- "Nevertheless, the binding and agonistic potential of epibatidine (1) had tremendous stimulating impact on the nACh receptors research. A number of ligands with high in vitro affinity for the α4β2 subtype have been radiolabeled, and tested for in vivo imaging of the brain nAChRs45678910. Remarkable high affinities to the nAChRs have been registered in simple azetidinyl-pyridyl and pyrrolidinyl-pyridyl ethers (A-85380 and A-84543,Fig. 1) . "
[Show abstract] [Hide abstract] ABSTRACT: 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.0Comments 136Citations
- "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., 1996Dukat et al., , 1999Dukat et al., , 2002a Saji et al., 1997; Lee et al., 2002), open-chain analogs (Lee et al., 2002), certain pyridyl ethers (Holladay et al., 1998a; Lin et al., 2001; Lee et al., 2002) and epibatidine ( Carroll et al., 2001a Carroll et al., , 2001b Carroll et al., , 2002 Avalos 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 inFig. "
[Show abstract] [Hide abstract] ABSTRACT: Cytisine (cy) is a potent and competitive partial agonist at alpha4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric alpha7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on recombinant human (h) alpha7, halpha4beta2 and halpha4beta4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at halpha7, halpha4beta2 and halpha4beta4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (halpha7, halpha4beta4 nACh receptors) to a marked increase (halpha4beta2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.0Comments 72Citations
- "Thus, the size of the substituent may be a limiting factor at α4 subunit-containing receptors. For example, 3-I-cy (Imming et al., 2001 ; this study) and 2-I-dechlor- oepibatidine (Carroll et al., 2001) are either equipotent with or less potent than their brominated counterparts, and the present results indicate that the affinity of 3-I- cy at α4β4 nACh receptors is less than that of cy. It might be surmised, therefore, that the putative halogenbinding hydrophobic region that accommodates the halogen substituent is not bulk-tolerant. "