A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α 7 and α 4 β 2 Nicotinic Acetylcholine Receptors.

Autor:	Xing H; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Andrud KW; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Soti F; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Rouchaud A; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Jahn SC; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Lu Z; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Cho YH; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Habibi S; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Corsino P; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Slavov S; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Rocca JR; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Lindstrom JM; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Lukas RJ; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.)., Kem WR; Department of Pharmacology and Therapeutics (H.X., K.W.A., F.S., A.R., S.C.J., Z.L., Y.-H.C., S.H., P.C., W.R.K.) and AMRIS, McKnight Brain Institute (J.R.R.), College of Medicine, University of Florida, Gainesville, Florida; National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (S.S.); Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania (J.M.L.); and Division of Neurobiology, Barrow Neurologic Institute, Phoenix, Arizona (R.J.L.) wrkem@ufl.edu.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2020 Aug; Vol. 98 (2), pp. 168-180. Date of Electronic Publication: 2020 May 30.
DOI:	10.1124/mol.119.118786
Abstrakt:	The two major nicotinic acetylcholine receptors (nAChRs) in the brain are the α 4 β 2 and α 7 subtypes. A "methyl scan" of the pyrrolidinium ring was used to detect differences in nicotine's interactions with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine's receptor interactions. Replacing the 1'- N -methyl with an ethyl group or adding a second 1'- N -methyl group significantly reduced interaction with α 4 β 2 but not α 7 receptors. The 2'-methylation uniquely enhanced binding and agonist potency at α 7 receptors. Although 3'- and 5'- trans -methylations were much better tolerated by α 7 receptors than α 4 β 2 receptors, 4'-methylation decreased potency and efficacy at α 7 receptors much more than at α 4 β 2 receptors. Whereas cis -5'-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, trans -5'-methylnicotine retained considerable α 7 receptor activity. Differences between the two 5'-methylated analogs of the potent pyridyl oxymethylene-bridged nicotine analog A84543 were consistent with what was found for the 5'-methylnicotines. Computer docking of the methylnicotines to the Lymnaea acetylcholine binding protein crystal structure containing two persistent waters predicted most of the changes in receptor affinity that were observed with methylation, particularly the lower affinities of the cis -methylnicotines. The much smaller effects of 1'-, 3'-, and 5'-methylations and the greater effects of 2'- and 4'-methylations on nicotine α 7 nAChR interaction might be exploited for the design of new drugs based on the nicotine scaffold. SIGNIFICANCE STATEMENT: Using a comprehensive "methyl scan" approach, we show that the orthosteric binding sites for acetylcholine and nicotine in the two major brain nicotinic acetylcholine receptors interact differently with the pyrrolidinium ring of nicotine, and we suggest reasons for the higher affinity of nicotine for the heteromeric receptor. Potential sites for nicotine structure modification were identified that may be useful in the design of new drugs targeting these receptors. (U.S. Government work not protected by U.S. copyright.)
Databáze:	MEDLINE
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