Metaphit inhibits dopamine transport and binding of [3H] methylphenidate, a proposed marker for the dopamine transport complex

Schweri, Margaret M.; Jacobson, Arthur E.; Lessor, Ralph A.; Rice, Kenner C.

doi:10.1016/0024-3205(89)90279-8

Cited by 12 publications

(11 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 3 H]Dopamine Uptake. Accumulation of [ 3 H]DA was determined as previously described . Briefly, 250 μL S 1 fraction prepared as described above from striatal tissue of anesthetized rats was diluted 4-fold with a modified Krebs-phosphate buffer (120 mM NaCl, 4.9 mM KCl, 1.2 mM MgSO 4 , 11 mM glucose, 0.16 mM Na 2 EDTA, 1.1 mM ascorbic acid, 0.01 mM pargyline, and 15.5 mM Na 2 PO 4 , equilibrated with 95% O 2 −5% CO 2 and adjusted to pH 7.4 with NaOH) and preincubated with 1100 μL Krebs-phosphate buffer and 100 μL vehicle or drug for 10 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-(Aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane Dopamine Uptake Inhibitors

et al. 1999

View full text Add to dashboard Cite

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.

show abstract

Section: Methodsmentioning

confidence: 99%

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-(Aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane Dopamine Uptake Inhibitors

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Accumulation of [ 3 H]dopamine was determined as previously described. 44 Briefly, 250 µL of an S1 fraction prepared as described above from striatal tissue of unanesthetized rats was diluted 4-fold with a modified Krebs-phosphate buffer (120 mM NaCl, 4.9 mM KCl, 1.2 mM MgSO4, 11 mM glucose, 0.16 mM Na2EDTA, 1.1 mM ascorbic acid, 0.01 mM pargyline, and 15.5 mM Na2PO4, equilibrated with 95% O2-5% CO2 and adjusted to pH 7.4 with HCl) and preincubated with 1100 µL of Krebs-phosphate buffer and 100 µL of vehicle or drug for 10 min at 37 °C prior to the addition of 50 µL of [ 3 H]dopamine hydrochloride (Dupont/NEN, Boston, MA, or Amersham Corp., Arlington Heights, IL) which had been previously diluted with sufficient cold dopamine hydrochloride to bring the specific activity to approximately 5 Ci/ mmol. The final concentration of dopamine in the samples was approximately 30 nM.…”

Section: -Amino-3-(2-pyridyl)indole (2)mentioning

confidence: 99%

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

et al. 1996

View full text Add to dashboard Cite

As part of a program to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (+/-)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m- or p-halo substituents were more potent than TMP, while electron-donating substituents caused little change or small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (+/-)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-,m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.

show abstract

“…Pharmacology. The IC 50 values for the inhibition of ligand binding to the DA, 5-HT, and NE transporters and the inhibition of [ 3 H]DA uptake into synaptosomes were determined according to established protocols and are shown in Table . Binding to the DA transporter was measured using [ 3 H]WIN 35,428 (WIN), to the 5-HT transporter using [ 3 H]paroxetine (PAR), and to the NE transporter using [ 3 H]nisoxetine (NIS).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-Substituted-6-amino-5-phenylbicyclo[2.2.2]octanes

et al. 1999

View full text Add to dashboard Cite

A series of 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes was synthesized and tested for inhibitor potency in [(3)H]WIN 35,428 (WIN) binding at the dopamine (DA) transporter and [(3)H]DA uptake assays. To demonstrate transporter selectivity for the compounds, inhibitor potency was also tested using [(3)H]nisoxetine and [(3)H]paroxetine binding assays for the norepinephrine (NE) and serotonin (5-HT) transporters, respectively. Synthesis was accomplished by bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine with 2-cyclohexenone to give a mixture of endo- and exo-trans-6-amino-5-phenylbicyclo[2.2. 2]octan-2-ones. The separated ketones were reduced to the four diastereomeric alcohols which were converted to acetyl and benzoyl esters. The ketones, alcohols, and acetyl esters generally have low affinity for the three transporters and do not effectively inhibit the uptake of [(3)H]DA. In all cases, the benzoates show significantly greater inhibition of WIN binding compared to the corresponding ketones, alcohols, or acetate esters. One compound, (1R/S,4R/S)-6R/S-(N,N-dimethylamino)-5R/S-phenylbicyclo[2.2. 2]oct-2S/R-yl benzoate, is almost as potent as cocaine in binding to the DA transporter (IC(50) = 270 nM versus 159 nM for cocaine). The C-2 epimer, (1R/S,4R/S)-6R/S-(N, N-dimethylamino)-5R/S-phenylbicyclo[2.2.2]oct-2R/S-yl benzoate, was selective and potent in binding to the 5-HT transporter (IC(50) = 53 nM versus 1050 nM for cocaine) as compared to the DA transporter (IC(50) = 358 nM). A preliminary molecular modeling study of the benzoyl esters indicates that their relative potencies in the WIN binding assay are not correlated to the nitrogen to benzoate phenyl (centroid) distance or to the deviation of the nitrogen from the plane defined by the benzoate ring.

show abstract

Metaphit inhibits dopamine transport and binding of [3H] methylphenidate, a proposed marker for the dopamine transport complex

Cited by 12 publications

References 12 publications

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-(Aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane Dopamine Uptake Inhibitors

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-(Aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane Dopamine Uptake Inhibitors

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

Synthesis and Pharmacology of Site-Specific Cocaine Abuse Treatment Agents: 2-Substituted-6-amino-5-phenylbicyclo[2.2.2]octanes

Contact Info

Product

Resources

About