Synthesis and ligand binding of cocaine isomers at the cocaine receptor

Carroll, F. Ivy; Lewin, Anita H.; Abraham, Philip; Parham, Karol; Boja, John W.; Kuhar, Michael J.

doi:10.1021/jm00107a003

Cited by 71 publications

(68 citation statements)

References 4 publications

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“…They provide evidence that some amino acids are of likely importance for both cocaine binding and dopamine transport while other cocaine binding residues might be dissected from those more important for dopamine transport. Structure-activity analyses of cocaine analog binding potencies are also consistent with the idea that some regions of cocaine that are homologous to features of dopamine are important for binding but that other features necessary for full cocaine analog potency do not have obvious homologs in the structure of dopamine (22)(23)(24). Characterization of the activities of structurally modified cocaine analogs at both wild-type and mutant DAT molecules could guide further development of agents with selective affinity for DAT sites important for cocaine binding and less involved in dopamine transport.…”

Section: Discussionsupporting

confidence: 63%

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Kitayama

Shimada

Hong

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

325

261

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Polar amino acids lying within three hydrophobic regions of the dopamine transporter (DAT) are analogous to those important for ligand recognition by catechoamilne receptors. Possible functional significance of these amino adds was examined by expressing DAT cDNAs mutated in these polar residues. Replacement of aspartate at position 79 with alanine, glycine, or glutamate dramatically reduced uptake of binding. These results demonstrate that aspartate and serine residues lying within the first and seventh hydrophobic putative transmembrane regions are crucial for DAT function and provide identification of residues differentially important for cocaine binding and for dopamine uptake.The dopamine transporter (DAT) aids in terminating dopaminergic neurotransmission by sodium-dependent reaccumulation of released dopamine into presynaptic neurons (1, 2) and is key for actions of cocaine and dopamine-specific neurotoxins such as 1-methyl-4-phenylpyridinium (MPP+) (3,4). cDNA cloning studies have recently elucidated the primary structures of DATs and other homologous members of the sodiumdependent neurotransmitter (plus) transporter family that are expressed in brain or kidney (5-12). However, the transporter sites recognizing neurotransmitters, sodium, neurotoxins, and drugs, including cocaine, are unknown. Clues as to DAT regions that could participate in dopamine recognition could come from studies of catecholamine binding to mutant adrenergic receptors (13, 14), which implicate aspartic acid and serine residues lying in hydrophobic regions in catecholamine binding. DAT contains a single aspartic acid residue in its first hydrophobic domain and serine residues in its seventh and eighth hydrophobic domains. We now report selective effects of mutations of these residues on DAT dopamine uptake and cocaine analog recognition. To more directly compare influences on these two end points, we have examined both binding and uptake in intact cell preparations. MATERIALS AND METHODS Single-stranded template for mutagenesis was derived from pcDNADAT1 (5); confirmed by DNA sequencing; and mutated by annealing oligonucleotides corresponding to the mutant sequences (Fig. 1)

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Section: Discussionsupporting

confidence: 63%

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Kitayama

Shimada

Hong

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

325

261

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“…One possibility for the failure of U69593 to attenuate drug seeking produced by amphetamine is that kappa-opioid receptor agonists interact with the presynaptic site that is specific to cocaine. In order to test this hypothesis, the effects of U69593 on cocaine seeking produced by the dopamine transporter inhibitor GBR 12909 (Anderson 1989;Baldo and Kelley 1991), or the cocaine analogs, WIN 35,428 (Boja et al 1990;Izenwasser et al 1993) and RTI-55 (Carroll et al 1991;Little et al 1993) and cocaine were compared.…”

Section: Susan Schenk · Brian Partridge · Toni S Shippenbergmentioning

confidence: 99%

Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593

2000

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The failure of U69593 to attenuate GBR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55-produced cocaine seeking raises the possibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter.

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“…Theoretical 3D structures of BChE (10 -12), of its complex with cocaine (9), and of the cocaine molecule itself have all been reported (13)(14)(15)(16). Nevertheless, the literature provides no explanation of how cocaine forms its Michaelis-Menten complex with BChE or why BChE hydrolyzes the unnatural stereoisomer much faster than the natural cocaine although their K m values are similar (9,17,18).…”

mentioning

confidence: 99%

Predicted Michaelis-Menten Complexes of Cocaine-Butyrylcholinesterase

Sun¹,

Yazal²,

Lockridge

et al. 2001

Journal of Biological Chemistry

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Butyrylcholinesterase (BChE) is important in cocaine metabolism, but it hydrolyzes (؊)-cocaine only one-two thousandth as fast as the unnatural (؉)-stereoisomer. A starting point in engineering BChE mutants that rapidly clear cocaine from the bloodstream, for overdose treatment, is to elucidate structural factors underlying the stereochemical difference in catalysis. Here, we report two three-dimensional Michaelis-Menten complexes of BChE liganded with natural and unnatural cocaine molecules, respectively, that were derived from molecular modeling and supported by experimental studies. Such complexes revealed that the benzoic ester group of both cocaine stereoisomers must rotate toward the catalytic Ser 198 for hydrolysis. Rotation of (؊)-cocaine appears to be hindered by interactions of its phenyl ring with Phe 329 and Trp 430 . These interactions do not occur with (؉)-cocaine. Because the rate of (؊)-cocaine hydrolysis is predicted to be determined mainly by the re-orientation step, it should not be greatly influenced by pH. In fact, measured rates of this reaction were nearly constant over the pH range from 5.5 to 8.5, despite large rate changes in hydrolysis of (؉)-cocaine. Our models can explain why BChE hydrolyzes (؉)-cocaine faster than (؊)-cocaine, and they suggest that mutations of certain residues in the catalytic site could greatly improve catalytic efficiency and the potential for detoxication.Cocaine overdose is a leading cause of death among urbandwelling young adults (1, 2). A new idea for treating cocaine overdose is to accelerate metabolic clearance by administering an appropriate hydrolase. Plasma butyrylcholinesterase (BChE) 1 can hydrolyze cocaine to ecgonine methyl ester and reportedly accounts for all the blood-borne cocaine hydrolysis activity in humans (3-5). Pretreatment with human BChE provides rats with substantial protection against cocaine-induced cardiac arrhythmia, hypertension, and locomotor hyperactivity (6). Exogenous BChE is also able to rescue rats given an overdose of cocaine (7). However, the k cat of BChE for (Ϫ)-cocaine is only 3.9 min Ϫ1, versus 33,900 min Ϫ1 for the optimal substrate, butyrylthiocholine. We estimate that timely detoxication of a cocaine overdose, with serum levels up to 20 mg/l (8), would require at least 100 mg of enzyme. An A328Y mutant of BChE developed by the trial and error approach (9) showed 4 -5-fold improvement in (Ϫ)-cocaine hydrolysis, but it is still not satisfactory for treatment of cocaine overdose. Because human BChE hydrolyzes synthetic (ϩ)-cocaine (see Fig. 1) about 2,000-fold faster than the natural (Ϫ)-cocaine (see Fig. 1) (9), elucidation of the structural factors responsible for the different catalytic rates may offer a rational strategy for engineering BChE mutants that can hydrolyze (Ϫ)-cocaine rapidly enough to treat cocaine overdose.Theoretical 3D structures of BChE (10 -12), of its complex with cocaine (9), and of the cocaine molecule itself have all been reported (13-16). Nevertheless, the literature provides no explanation o...

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Synthesis and ligand binding of cocaine isomers at the cocaine receptor

Cited by 71 publications

References 4 publications

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593

Predicted Michaelis-Menten Complexes of Cocaine-Butyrylcholinesterase

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