Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by .alpha.-amino acid esters of phenethyl alcohols

Lindberg, U. H.; Thorberg, Seth Olof; Bengtsson, Stefan; Renyi, A. L.; Ross, Svante B.; Ögren, Sven Ove

doi:10.1021/jm00203a008

Cited by 94 publications

(47 citation statements)

References 19 publications

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“…Indeed it was found that the antagonism of the harmaline-induced increase in cGMP in cerebellum in vivo was obtained in the same dose range (5-20 mg/kg) that alaproclate inhibits 5-HT uptake in vivo (Ogren e t al. 1984) which is in accordance with the similar in vitro affinities of alaproclate for the NMDA channel binding site (Ki=0.5 pM in hippocampus) (Svensson & Ross 1995) and for the 5-HT uptake site (Ki=0.13 pM in hippocampal synaptosomes) (Lindberg et al 1978).…”

Section: Discussionsupporting

confidence: 78%

“…The 5-HT uptake inhibitory action of alaproclate does not seem to be involved in the antagonism of the NMDA receptor-stimulated cGMP production since the alaproclate analogue GEA-857, that causes very weak if any inhibition of 5-HT uptake in vitro and in vivo (Lindberg et al 1978, Ogren e t al. 1992), was at least as potent as alaproclate in antagonizing the harmaline-induced increase in cGMP Both of these compounds block K+ channels (Hedlund 1987;Hedlund & Andersen 1989;Hedlund & Ogren 1992) but this ability does not seem to be involved in the effect examined in the present study since the unselective K+-channel blocker 4-aminopyridine in the contrary to alaproclate and GEA857 per se caused a pronounced increase in cGMP Furthermore, Svensson e t al.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments have shown that alaproclate, an antidepressant 5-HT uptake inhibitor, (Lindberg et al 1978;Ogren et al 1984) antagonizes NMDA receptor coupled Ca2+ influx in rat cerebellar neurones (Wilkinson et al 1994), blocks with an open channel mechanism NMDA receptor currents in rat hippocampal neurones (Svensson et al 1994) and inhibits binding of 3H-dizocilpine (( +)-MK-801) to rat cerebral cortical membranes (Svensson & Ross 1995). All these observations indicate that alaproclate is a moderately potent uncompetitive NMDA receptor antagonist with an potency similar to that seen at the neuronal 5-HT transporter (Lindberg et al 1978).…”

Section: Discussionmentioning

confidence: 99%

“…Alaproclate is a selective inhibitor of 5-hydroxytryptamine (5-HT) uptake (Lindberg et al 1978) with potential antidepressive action (Aberg-Wistedt et al 1985). Several studies have shown that alaproclate can also enhance cholinergic responses to muscarinic agonists, an effect that does not seem to be due to the inhibition of 5-HT uptake (Ogren et al 1985;Danielsson et al 1986).…”

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confidence: 99%

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NMDA Receptor‐Mediated Increase in Cyclic GMP in the Rat Cerebellum in vivo is Blocked by Alaproclate and GEA‐857

Hu¹,

Ross²

1997

Pharmacology & Toxicology

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Abstract:The effects of alaproclate and GEA-857 (2-(4-chlorophenyl)-1,1 -dimethylethyl 2-amino-3-methylbutanoate) on the production of cyclic GMP in the rat cerebellum in vivo induced by stimulation of N-methyl-D-aspartate (NMDA) receptors were studied. Alaproclate per se at a dose of 20 mg/kg subcutaneously. did not influence the basal cGMP level. The increase in cGMP induced by harmaline (20 mg/kg subcutaneously) was dose-dependently antagonized by alaproclate ( 5 4 0 mgikg subcutaneously). S-(-)-Naproclate was 2 -5 times more potent than the R-(+)-enantiomer. GEA-857 which in contrast to alaproclate is a very weak 5-HT uptake inhibitor shared the ability of alaproclate to inhibit the effect of harmaline on cGMP accumulation with similar potency to S-(-)-alaproclate. Alaproclate at 15 mg/kg subcutaneously blocked the increase in cGMP in cerebellum caused by NMDA itself at 200 mg/kg subcutaneously. In contrast to alaproclate, the K+ channel antagonist, 4-aminopyridine, 5 mgikg subcutaneously, produced per se an increase in cGMP levels in the rat cerebellum by 300% which was antagonized by the NMDA receptor antagonists, dizocilpine, phencyclidine and (2)-CCP, the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester and by alaproclate. Alaproclate and GEA-857 antagonized seizures induced by NMDA, 200 mgikg subcutaneously at doses similar to those antagonizing the harmaline-and NMDA-induced elevation of cerebellar cGMP Neither alaproclate nor GEA-857 caused any behavioural effects typical for uncompetitive NMDA receptor antagonists except a slight increase in motor activity and sniffing. The effect of alaproclate on the NMDA receptor-mediated increase in cGMP in rat cerebellum in vivo might be due to blockade of the cation channel of the NMDA receptor complex previously observed in in vitro experiments and these compounds seems to belong to the group of low-affinity uncompetitive NMDA receptor antagonists that might have clinical interest.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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NMDA Receptor‐Mediated Increase in Cyclic GMP in the Rat Cerebellum in vivo is Blocked by Alaproclate and GEA‐857

Hu¹,

Ross²

1997

Pharmacology & Toxicology

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“…The effects of a 5-HT uptake inhibitor, alaproclate, and a 5-HT direct agonist, quipazine, on cocaine self-administration were characterized to determine whether serotonergic modulation of the behavioral-stimulant effects of cocaine reported previously extends to its reinforcing effects. Alaproclate has high nanomolar affinity for the 5-HT transporter and greater than 50-fold selectivity for the 5-HT transporter compared with DA and norepinephrine transporters (Lindberg et al, 1978). Quipazine is a nonselective 5-HT agonist with low nanomolar affinity for 5-HT 2 binding sites (Glennon, 1986).…”

mentioning

confidence: 99%

Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys

Czoty¹,

Ginsburg²,

Howell³

2002

J Pharmacol Exp Ther

108

100

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Preclinical studies have documented that serotonin (5-HT) can modulate the behavioral effects of cocaine. The present study examined the ability of 5-HT to attenuate the reinforcing and neurochemical effects of cocaine in nonhuman primates. In squirrel monkeys trained to self-administer cocaine (0.1 and 0.3 mg/injection) under a second-order schedule of i.v. drug delivery, the 5-HT uptake inhibitor alaproclate (3.0 and 10.0 mg/kg) and the 5-HT direct agonist quipazine (0.3-1.0 mg/kg) decreased response rates at doses that had no significant effect on behavior maintained by an identical schedule of stimulus termination. The neurochemical bases of the observed drug interactions on behavior were investigated further using in vivo microdialysis techniques in a separate group of awake monkeys to monitor drug-induced changes in extracellular dopamine (DA). Cocaine (1.0 mg/kg) elevated the concentration of DA in the caudate nucleus to approximately 300% of basal levels. Pretreatment with alaproclate or quipazine attenuated cocaine-induced increases in extracellular DA at the same pretreatment doses that decreased cocaine self-administration. The results obtained suggest that increasing brain 5-HT activity can attenuate the reinforcing effects of cocaine, ostensibly by decreasing the ability of cocaine to elevate extracellular DA in brain areas that mediate the behavioral effects. These findings extend those reported previously for the behavioral-stimulant effects of cocaine and identify a potential neurochemical mechanism underlying drug interactions on behavior.Abuse of stimulant drugs such as cocaine persists as a major health problem in the United States (Chilcoat and Johanson, 1998). Clearly, there is a great need for pharmacological treatments to combat abuse of these drugs; however, no pharmacotherapy has demonstrated sufficient efficacy for widespread clinical use (Carroll et al., 1999). A better understanding of the effects of cocaine on central nervous system neurochemistry will help identify effective approaches in developing medications for treating cocaine dependence.The behavioral-stimulant and reinforcing effects of cocaine have been linked to its ability to enhance dopaminergic neurotransmission by inhibiting DA uptake via transporter blockade (Ritz et al., 1987). The affinities of several cocainelike drugs for DA transporter correlate well with their potencies for supporting self-administration behavior (Ritz et al., 1987;Bergman et al., 1989). In humans, a significant correlation has been observed between DA transporter binding and the intensity of subjective effects produced by intravenous cocaine (Volkow et al., 1997). Cocaine affects neurotransmission in various brain DA systems, leading to a variety of behavioral effects. For example, the DA neurons of the substantia nigra pars compacta project to the caudate nucleus and putamen, the primate homologues of the rodent dorsal striatum (Parent et al., 1995), to modulate motor function. Facilitation of DA transmission in the nigrostriatal system...

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Effects of Antidepressant Treatments on Platelet Tritiated Imipramine Binding in Major Depressive Disorder

Wagner

Åberg‐Wistedt²,

Åsberg³

et al. 1987

Arch Gen Psychiatry

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Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by .alpha.-amino acid esters of phenethyl alcohols

Cited by 94 publications

References 19 publications

NMDA Receptor‐Mediated Increase in Cyclic GMP in the Rat Cerebellum in vivo is Blocked by Alaproclate and GEA‐857

NMDA Receptor‐Mediated Increase in Cyclic GMP in the Rat Cerebellum in vivo is Blocked by Alaproclate and GEA‐857

Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys

Effects of Antidepressant Treatments on Platelet Tritiated Imipramine Binding in Major Depressive Disorder

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