Interactions of cocaine and cocaine congeners with sodium channels

Matthews, John C.; Collins, Ann

doi:10.1016/0006-2952(83)90523-3

Cited by 57 publications

(30 citation statements)

References 11 publications

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“…3). Previously, cocaine had been demonstrated to have an IC 50 of 6 M and lidocaine an IC 50 of 73.6 Ϯ 10 M as inhibitors of veratridineinduced Na ϩ flux (Matthews and Collins, 1983;Deffois et al, 1996). This potency of cocaine and lidocaine is therefore in good agreement with the data presented here.…”

Section: Methodssupporting

confidence: 92%

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Reith

Ali

Hashim

et al. 2012

J Pharmacol Exp Ther

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Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(Ϫ)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3-and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na ϩ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.

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Section: Methodssupporting

confidence: 92%

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Reith

Ali

Hashim

et al. 2012

J Pharmacol Exp Ther

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“…1. Detailed structures of cocaine homologues can be found in Matthews and Collins (1983). The relevant chiral carbons are asterized to indicate the location of the R (rectus) and S (sinister) forms according to Cahn-Ingold-Prelog configuration system.…”

Section: Mepivacainementioning

confidence: 99%

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Wang

1990

The Journal of General Physiology

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Several local anesthetics (LA) have been previously shown to block muscle batrachotoxin (BTX)-activated Na § channels in planar bilayers. The mean dwell time of different LA drugs, however, varies widely, from <10 ms to longer than several seconds. In this study, we have examined the structural determinants that govern the dwell time, the binding affinity, and the stereoselectivity of LA drugs using cocaine and bupivacaine homologues, RAC compounds, and their available stereoisomers. Our results from the structure-activity experiments reveal that (a) there are two apparent hydrophobic binding domains present in the LA binding site; one interacts with the aromatic moiety of the LA drugs, and the other interacts with the alkyl group attached to the tertiary amine of the LA drugs; (b) the LA mean dwell time and the binding affinity are largely determined by the hydrophobic interactions; (c) the LA binding site is highly stereoselective, with a difference in K D values over 50-and 6-fold for (+/-) cocaine and (+/-) bupivacaine, respectively; (d) the cocaine stereoselectivity is comparable among muscle, brain, and heart BTX-activated Na + channels; and finally and most unexpectedly, (e) the stereoselectivity of LA drugs in BTX-activated Na + channels appears greatly different from that reported in normal Na + channels. Possible explanations for this difference are discussed.

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“…Second, it reduces the inward Na+ current by inhibiting the sodium channel in the sarcolemma, producing a local anaesthetic effect (Hale et al, 1989;Przywara & Dambach, 1989;Billman, 1990). Reduction of the inward Na+ current (Matthews & Collins, 1983;Reith et al, 1986;Reiter, 1988) would reduce the subsequent inward Ca2`current (Reiter, 1988;Stewart et al, 1991). The negative inotropic effect of cocaine on cardiac muscle from a variety of different mammalian species appears to be predominantly produced by the local anaesthetic action.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of cocaine and cocaethylene on intracellular Ca²⁴⁺ and myocardial contraction in cardiac myocytes

Qiu

Morgan

1993

British J Pharmacology

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1 Isolated cardiac myocytes of the ferret were used to investigate the influence of cocaine and cocaethylene on the intracellular Ca2`transient indicated by the indo-l 405/480 nm ratio signal, and peak cell shortening.2 Both cocaine and cocaethylene produced significant decreases in peak intracellular Ca2`and peak cell shortening in a dose-dependent manner. Of interest, (1) the minimally effective dose of cocaethylene was ten fold lower (10-8 M versus 10-M) than that of cocaine; (2) the log EC, of cocaethylene was -5.99 ± 0.13 (1.0 x 10-6M), which was about ten fold lower than that of cocaine (-5.02 ± 0.11, 9.6 X 10-6 M); and (3) 1 x 10-4 M cocaethylene decreased the contraction amplitude by 71 ± 7%, while the same concentration of cocaine decreased the amplitude only by 55 ± 5%, indicating that cocaethylene is more potent than cocaine. 3 The negative inotropic effects of either cocaine or cocaethylene could be overcome by noradrenaline (5 gM) or calcium.4 In contrast to cocaine, cocaethylene shifted the peak [Ca2+]i-peak shortening relationship downward, indicating that cocaethylene decreased myofilament Ca2+-responsiveness. 5 These data indicate that both cocaine and cocaethylene act directly on cardiac myocytes to produce a negative inotropic effect that is due to decreased Ca2+ availability. In contrast to cocaine, cocaethylene produces more potent inhibition by an additional action to decrease myofilament Ca2+-responsiveness.

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Interactions of cocaine and cocaine congeners with sodium channels

Cited by 57 publications

References 11 publications

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Differential effects of cocaine and cocaethylene on intracellular Ca²⁴⁺ and myocardial contraction in cardiac myocytes

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Interactions of cocaine and cocaine congeners with sodium channels

Cited by 57 publications

References 11 publications

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Differential effects of cocaine and cocaethylene on intracellular Ca24+ and myocardial contraction in cardiac myocytes

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Differential effects of cocaine and cocaethylene on intracellular Ca²⁴⁺ and myocardial contraction in cardiac myocytes