Functional diversity among 5-substituted nicotine analogs; in vitro and in vivo investigations.
Two 5-substituted derivatives of nicotine (nicotinic acetylcholine receptor: K(i)=2.4 nM) were synthesized and evaluated: 5-bromonicotine (K(i)=6.9 nM) and 5-methoxynicotine (K(i)=14.3 nM). Despite their high affinity, neither 5-bromonicotine nor 5-methoxynicotine mimicked nicotine in producing antinociceptive (tail-flick, hotplate), hypolocomotor, or hypothermic effects in mice. Neither agent antagonized the hypolocomotor actions of nicotine, whereas 5-methoxynicotine, but not 5-bromonicotine, antagonized the antinociceptive (tail-flick) activity of nicotine in a dose-related manner. In tests of stimulus generalization using rats trained to discriminate 0.6 mg/kg of (-)-nicotine from vehicle, 5-bromonicotine substituted for nicotine. Further evaluation of 5-bromonicotine indicated that it might be a partial agonist at alpha4beta2 receptors (stimulation of Rb(+) efflux; alpha4beta2 receptors expressed in oocytes) and at alpha3-containing nicotinic acetylcholine receptors (synaptosomal dopamine release). Thus, 5-bromonicotine might be acting as a partial agonist at alpha4beta2 receptors and/or some of its effects might be related to interactions with non-alpha4beta2 receptors. Clearly, the effects of 5-bromonicotine and 5-methoxynicotine are different from those of nicotine, and from one another. These actions demonstrate that substitution at the 5-position of nicotine exerts a profound influence on the pharmacological profile as well as agonist/antagonist properties of nicotine.
Dukat
Małgorzata
M
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Box 980540 VCU, Richmond, VA 23298-0540, USA. mdukat@hsc.vcu.edu
Damaj
Imad M
IM
Young
Richard
R
Vann
Robert
R
Collins
Allan C
AC
Marks
Michael J
MJ
Martin
Billy R
BR
Glennon
Richard A
RA
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology*; D009539:Nicotinic Acids / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism
C450043:5-methoxynicotine; D000700:Analgesics; D009539:Nicotinic Acids; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C097384:5-bromonicotinic acid; D009538:Nicotine; D012413:Rubidium; D004298:Dopamine