Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2-exo-2-(2',3'-disubstituted 5'-pyridinyl)-7-azabicyclo[2.2.1]heptanes: Epibatidine Analogues

J Med Chem. 2002 Oct 10;45(21):4755-61. doi: 10.1021/jm0202268.

Abstract

A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2'- and the 3'-positions showed affinities at the nAChR similar to epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3'-Amino-2'-chloro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing amino group in the 3'-position, produced the highest affinity. Compound 2i was also the most selective epibatidine analogue with a K(i) of 0.001 nM at alphabeta nAChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K(i) ratio of 14,000, twice that of epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception with AD(50) values below 1 microg/kg. Surprisingly, this same compound was also an agonist at higher doses (ED(50) approximately 20 microg/kg). Thus, the addition of the 3'-amino group to epibatidine confers potent antagonist activity to the compound with little effect on agonist activity. 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combined with a 3'-bromo or 3'-iodo group showed in vitro and in vivo nAChR properties similar to nicotine.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Non-Narcotic / chemical synthesis*
  • Analgesics, Non-Narcotic / chemistry
  • Analgesics, Non-Narcotic / pharmacology
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cerebral Cortex / metabolism
  • In Vitro Techniques
  • Ligands
  • Male
  • Nicotinic Agonists / chemical synthesis*
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology
  • Pain Measurement
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Nicotinic / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2-(2'-chloro-3'-amino-5'-pyridinyl)-7-azabicyclo(2.2.1)heptane
  • Analgesics, Non-Narcotic
  • Bridged Bicyclo Compounds, Heterocyclic
  • Ligands
  • Nicotinic Agonists
  • Pyridines
  • Receptors, Nicotinic
  • epibatidine