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.