QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.084376v1 314/2/906    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nightingale, B. Articles by Rothman, R. B. Search for Related Content PubMed PubMed Citation Articles by Nightingale, B. Articles by Rothman, R. B.

NEUROPHARMACOLOGY

Studies of the Biogenic Amine Transporters. XI. Identification of a 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) Analog That Allosterically Modulates the Serotonin Transporter

Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (B.N., C.M.D., R.B.R.); and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland (T.L.B., E.G., W.J.C., A.E.J., K.C.R.)

Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine analogs (4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1-099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. -(4'-¹²⁵Iodophenyl)tropan-2-carboxylic acid methyl ester ([¹²⁵I]RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K_i = 439 nM), was inactive at NET binding ([³H]nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [¹²⁵I]RTI-55 binding to hSERT with an extrapolated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K_d and B_max of [¹²⁵I]RTI-55 binding to hSERT, we found that TB-1-099 decreased the B_max in a dose-dependent manner and affected the apparent K_d in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K_d but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [³H]5-HT, but not [³H]dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [¹²⁵I]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [¹²⁵I]RTI-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function.

Address correspondence to: Dr. Richard B. Rothman, CPS, DIR, NIDA, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: rrothman{at}intra.nida.nih.gov

This article has been cited by other articles:

				R. B. Rothman, C. M. Dersch, S. Ananthan, and J. S. Partilla Studies of the Biogenic Amine Transporters. 13. Identification of "Agonist" and "Antagonist" Allosteric Modulators of Amphetamine-Induced Dopamine Release J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 718 - 728. [Abstract] [Full Text] [PDF]

				J. J. Pariser, J. S. Partilla, C. M. Dersch, S. Ananthan, and R. B. Rothman Studies of the Biogenic Amine Transporters. 12. Identification of Novel Partial Inhibitors of Amphetamine-Induced Dopamine Release J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 286 - 295. [Abstract] [Full Text] [PDF]

				R. B. Rothman, D. L. Murphy, H. Xu, J. A. Godin, C. M. Dersch, J. S. Partilla, K. Tidgewell, M. Schmidt, and T. E. Prisinzano Salvinorin A: Allosteric Interactions at the {micro}-Opioid Receptor J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 801 - 810. [Abstract] [Full Text] [PDF]