Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Avalos, Melva; Parker, Michael; Maddox, Floyd N.; Carroll, F. Ivy; Luetje, Charles W.

doi:10.1124/jpet.102.035899

Cited by 34 publications

(32 citation statements)

References 21 publications

(26 reference statements)

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“…because equilibrium binding and functional characterization reflect the affinity of the agonist for the desensitized and activated state of the nAChR, respectively, a clear-cut correlation between affinity and potency cannot be assumed. In agreement with this, very different findings on the correlation between binding and functional data have been reported from studies on epibatidine and cytisine analogs at various recombinant neuronal nAChRs (Avalos et al, 2002;Slater et al, 2003). In this study, we observed a clear correlation between binding and functional properties of the compounds at the ␣3␤4 nAChR (Fig.…”

Section: Discussionsupporting

confidence: 77%

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Jensen¹,

Mikkelsen²,

Frølund³

et al. 2003

Mol Pharmacol

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The classic muscarinic acetylcholine receptor (mAChR) agonist carbamoylcholine (carbachol) does not seem to be the most obvious lead for the development of selective ligands at nicotinic acetylcholine receptors (nAChRs). In the past, however, N-methylations of carbachol have provided N-methylcarbamoylcholine and N,N-dimethylcarbamoylcholine (DMCC), which predominantly display nicotinic activity. In this study, 12 homologous analogs of DMCC and its corresponding tertiary amine, N,N-dimethylcarbamoyl-N,N-dimethylaminoethanol, were synthesized and their binding affinities to native mAChR and nAChR sites estimated. One of the compounds in the series, 3-N,N-dimethylaminobutyl-N,N-dimethylcarbamate (7), displayed low nanomolar binding affinity to nAChRs and a 400-fold selectivity for nAChRs over mAChRs. Hence, a new series of compounds was synthesized in which alkyl and aryl groups and different ring systems were introduced in the carbamate moiety of 7. In a [3 H]epibatidine binding assay, the K i values of 7 and its analogs at rat ␣2␤2, ␣4␤2, ␣2␤4, ␣3␤4, and ␣4␤4 nAChRs, stably expressed in mammalian cell lines, ranged from low nanomolar to midmicromolar concentrations, whereas all of the compounds displayed weak binding to an ␣7/5-HT 3 chimera and to native mAChRs. Compound 7 and its analogs were determined to be agonists at the ␣3␤4 nAChR subtype. This series includes the most potent and selective nicotinic agonists structurally derived from ACh to date. Furthermore, the compounds are tertiary amines, implying some advantages in terms of bioavailability pertinent to future in vivo pharmacological studies. Finally, observations made in the study hold promising perspectives for future development of ligands selective for specific nAChR subtypes.The neurotransmitter acetylcholine (ACh) exerts its effects in the central and peripheral nervous systems through two distinct classes of receptors, the muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively). The five cloned mAChR subtypes, m1 to m5, are members of the G-protein-coupled receptor superfamily and mediate their effects through intracellular metabolic cascades (Eglen et al., 2001). In contrast, the nAChRs belong to a superfamily of ligand-gated ion channels that also includes receptors for GABA, glycine, and serotonin (5-HT) (Corringer et al., 2000;Karlin, 2002). The nAChRs are involved in a wide array of physiological functions; over the years, nicotinic ligands have attracted considerable interest as potential therapeutics in the treatment of pain and a number of neurodegenerative and psychiatric disorders (Gotti et al., 1997;Lindstrom, 1997; Arneric and Brioni, 1999;Levin, 2002). Furthermore, nicotine replacement therapy has become the predominant treatment for smoking cessation (Arneric and Brioni, 1999;Levin, 2002).The nAChR is a transmembrane allosteric protein complex composed of five subunits. So far, 17 nAChR subunits have been cloned and divided into five muscle-type subunits (␣1, ␤1, ␥, ⑀, and ␦) and 12 neuronal subun...

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Section: Discussionsupporting

confidence: 77%

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Jensen¹,

Mikkelsen²,

Frølund³

et al. 2003

Mol Pharmacol

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“…As expected from previous studies with fluoro-and norchloro-analogues of epibatidine [116] , the newly-designed homoepibatidine analogues have 20-to 60-fold lower and 1.55 μg/kg for (+)-fl ubatine after i.v. injection [119] .…”

Section: Fig 2 Key Molecules For Development Of New Pet Radiotracersupporting

confidence: 82%

“…As expected from previous studies with fluoro-and norchloro-analogues of epibatidine [116] , the newly-designed homoepibatidine analogues have 20-to 60-fold lower affinities to ganglionic α3β4 nAChRs than to the α4β2 subtype [117] . For fl ubatine, the increase in subtype selectivity seemingly results in decreased pharmacological sideeffects compared to epibatidine.…”

Section: New Compoundssupporting

confidence: 81%

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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“…The binding affinity derived from this type of assay is primarily the affinity of the ligand for the desensitized state(s) of the receptor. Unfortunately, large differences in affinity observed in equilibrium binding assays are generally not observed in functional assays, and the rank order of affinities do not necessarily correlate with the rank orders of functional potency or efficacy (Avalos et al, 2002;Jensen et al, 2005). Thus, we find that the functional potency of varenicline at ␣4␤2, ␣3␤4, and ␣7 receptors varies by 24-fold or less.…”

Section: Downloaded Frommentioning

confidence: 79%

Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

Mihalak¹,

Carroll²,

Luetje³

2006

Mol Pharmacol

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524

465

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Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of ␣4␤2 receptors, and in equilibrium binding assays, it is highly selective for the ␣4␤2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at ␣4␤2 receptors, with an EC 50 of 2.3 Ϯ 0.3 M and an efficacy (relative to acetylcholine) of 13.4 Ϯ 0.4%. Varenicline has lower potency and higher efficacy at ␣3␤4 receptors, with an EC 50 of 55 Ϯ 8 M and an efficacy of 75 Ϯ 6%. Varenicline also seems to be a weak partial agonist at ␣3␤2 and ␣6-containing receptors, with an efficacy Ͻ10%. It is remarkable that varenicline is a potent, full agonist at ␣7 receptors with an EC 50 of 18 Ϯ 6 M and an efficacy of 93 Ϯ 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric ␣7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

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Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

Cited by 34 publications

References 21 publications

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

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