Chain-lengthened and imidazoline analogues of nicotine.
Analogues of nicotine (1) and azanicotine (3) were prepared with an additional methylene group inserted between the two rings (i.e., homonicotine and homoazanicotine; 6 and 5, respectively). Although 6 (Ki = 3110 nM) and 3 (Ki = 206 nM) bind at nACh receptors with > or = 100-fold lower affinity than nicotine (Ki = 2.1 nM), 5 displays high affinity (Ki = 7.8 nM). Like nicotine (ED50 = 12 microg/mouse), both 3 and 5 (ED50 = 21 and 19 microg/mouse, respectively) produced antinociceptive activity in the tail-flick assay following intrathecal administration. The antinociceptive actions of 3 and 5, unlike those of nicotine, were not antagonized by mecamylamine. Compounds 3 and 5 might represent novel analgesic agents that act via a non-nicotinic mechanism, or via a nicotinic mechanism that is distinct from that mediating the antinociceptive actions of nicotine.
Ferretti
G
G
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Dukat
M
M
Giannella
M
M
Piergentili
A
A
Pigini
M
M
Quaglia
W
W
Damaj
M I
MI
Martin
B R
BR
Glennon
R A
RA
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D009538:Nicotine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats
D000700:Analgesics; D007093:Imidazoles; D009538:Nicotine