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Lapinsky D.J.,Duquesne University | Yarravarapu N.,Duquesne University | Nolan T.L.,Duquesne University | Surratt C.K.,Duquesne University | And 5 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

The development of photoaffinity ligands for determining covalent points of attachment to the dopamine transporter (DAT) has predominantly focused on tropane-based compounds bearing variable-length linkers between the photoreactive group and the inhibitor pharmacophore. To expand the array of photoprobes useful for mapping inhibitor-binding pockets within the DAT, a compact nontropane ligand was synthesized featuring a photoreactive azide and iodine tag directly attached to the aromatic ring of (±)-threo- methylphenidate. (±)-threo-4-Azido-3-iodomethylphenidate [(±)-6; Ki = 4.0 ± 0.8 nM] displayed high affinity for hDAT. Moreover, a radioiodinated analogue of (±)-6 demonstrated covalent ligation to the DAT in cultured cells and rat striatal membranes, thus suggesting the potential utility of this photoprobe in DAT structure-function studies. © 2012 American Chemical Society. Source

Lapinsky D.J.,Duquesne University | Aggarwal S.,Duquesne University | Nolan T.L.,Duquesne University | Surratt C.K.,Duquesne University | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Towards addressing the knowledge gap of how bupropion interacts with the dopamine transporter (DAT) and nicotinic acetylcholine receptors (nAChRs), a ligand was synthesized in which the chlorine of bupropion was isosterically replaced with an iodine and a photoreactive azide was added to the 4′-position of the aromatic ring. Analog (±)-3 (SADU-3-72) demonstrated modest DAT and α4β2 nAChR affinity. A radioiodinated version was shown to bind covalently to hDAT expressed in cultured cells and affinity-purified, lipid-reincorporated human α4β2 neuronal nAChRs. Co-incubation of (±)-[ 125I]-3 with non-radioactive (±)-bupropion or (-)-cocaine blocked labeling of these proteins. Compound (±)-[ 125I]-3 represents the first successful example of a DAT and nAChR photoaffinity ligand based on the bupropion scaffold. Such ligands are expected to assist in mapping bupropion-binding pockets within plasma membrane monoamine transporters and ligand-gated nAChR ion channels. © 2011 Elsevier Ltd. All rights reserved. Source

Rodvelt K.R.,University of Missouri | Lever S.Z.,University of Missouri | Lever J.R.,University of Missouri | Lever J.R.,Harry uman Veterans Administration Medical Center | And 3 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

Cocaine exhibits preferential (~ 15-fold) affinity for σ 1 over σ 2 sigma receptors, and previous research has shown an interaction of σ 1 receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants. © 2010 Elsevier Inc. Source

Fan K.-H.,University of Missouri | Lever J.R.,University of Missouri | Lever J.R.,Harry uman Veterans Administration Medical Center | Lever S.Z.,University of Missouri
Bioorganic and Medicinal Chemistry | Year: 2011

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2, 3-dimethoxy-benzamide (1) is one of the most potent and selective σ2 receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5-7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their σ1/σ2 binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the five-membered ring congener of 1 displayed a higher σ1/σ2 selectivity, derived from a higher σ2 affinity and a lower σ1 affinity. Positioning the nitrogen adjacent to the aromatic ring in the five-membered and six-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional σ2 receptor binding affinity and selectivity for this active series. © 2011 Elsevier B.V. All rights reserved. Source

Sage A.S.,University of Missouri | Oelrichs C.E.,University of Missouri | Davis D.C.,University of Missouri | Fan K.-H.,University of Missouri | And 5 more authors.
Pharmacology Biochemistry and Behavior | Year: 2013

The present study examined N-phenylpropyl-N'-substituted piperazine sigma receptor ligands on cocaineinduced changes in locomotor activity in mice. Previous reports indicate that N-phenylpropyl-N'-(4- methoxybenzyl)piperazine (Nahas-3h), N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine (YZ-067), and N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) bind with high affinity (Ki values ≈ 1 nM) to σ1 sigma receptors. YZ-067 and YZ-185 are known to attenuate cocaine-induced convulsions, while Nahas-3h has not been tested in behavioral studies. Nahas-3h significantly attenuated cocaine-induced hyperactivity. YZ- 067 decreased the effect of cocaine in a dose-dependentmanner. Interestingly, YZ-185 inhibited cocaine's effect at higher doses, but enhanced cocaine's effect at a low dose. The YZ-185 inhibition of cocaine-induced hyperactivity was not surmounted by increasing the cocaine dose. Overall, this study is consistent with previous work showing the ability of certain sigma receptor ligands to affect cocaine-induced hyperactivity. Further, subtle alterations of ligand structure and the specific dosage levels employed influence the behavioral effects observed, with a 3-methoxy substituent apparently conferring the ability of a ligand to enhance cocaine's locomotor stimulatory effects. © 2013 Elsevier Inc. All rights reserved. Source

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