A conformational study of R-alaproclate, a new selecetive inhibitor of neuronal 5-hydroxytryptamine uptake

Lindberg, U. H.; Ross, Svante B.; Thorberg, Seth-Olof; Ögren, Sven Ove; MALMROS, G.; Wagner, Annemarie

doi:10.1016/0040-4039(78)80042-2

Cited by 8 publications

(2 citation statements)

References 5 publications

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“…A recent conformational study of the R enantiomer of alaproclate, compound 2, by a single-crystal x-ray determination and energy calculations gives support for this supposition. 30 It is interesting to note that this conformation of 5-HT is close to a gauche form reported for the crystal structure of serotonin picrate, where stacking interactions of a charge-transfer type between the indole and picric acid nuclei were indicated. 31 It appears therefore possible that the favored conformation of 5-HT for binding to the uptake site is the gauche form, in which the side chain is approximately perpendicular to the indole plane and the terminal nitrogen is bent toward the 2 position of the indole in a staggered conformation.…”

supporting

confidence: 75%

“…This compound was prepared from 2-(4methoxyphenyl)ethanol and L-4-methyl-2,5-oxazolidinedione in analogy with the method described for compound 16. 2-(4-Chlorophenyl)-l, 1-dimethylethyl 2-Amino-3phenylpropanoate Hydrochloride (21). l-(4-Chlorophenyl)-2-methyl-2-propanol (5.54 g, 30.0 mmol; see compound 1) was mixed with dimethylaniline (3.64 g, 30.0 mmol) and dichloromethane (15 mL). The solution was cooled and 2bromo-3-phenylpropanoic acid bromide (prepared in analogy with a method of Cason et al37) (13.1 g, 45.0 mmol) was added dropwise during 25 min.…”

Section: Methodsmentioning

confidence: 99%

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

Lindberg¹,

Thorberg²,

Bengtsson³

et al. 1978

J. Med. Chem.

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A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride (I, IV)], was selected for further studies as a potential antidepressant agent. A discussion on structure--activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.

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supporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

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

Lindberg¹,

Thorberg²,

Bengtsson³

et al. 1978

J. Med. Chem.

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ChemInform Abstract: A CONFORMATIONAL STUDY OF R‐ALAPROCLATE, A NEW SELECTIVE INHIBITOR OF NEURONAL 5‐HYDROXYTRYPTAMINE UPTAKE

Lindberg¹,

Ross²,

Thorberg³

et al. 1978

Chemischer Informationsdienst

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Evidence for selective serotonergic receptor involvement in p-chloroamphetamine-induced antinociception

Ögren

Berge

1985

Naunyn-Schmiedeberg's Arch. Pharmacol.

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Administration of the serotonin (5-HT) releasing compound p-chloroamphetamine (PCA; 2.5 mg/kg) induced potent analgesia in rats tested with the hot plate method. The analgesia was prevented by pretreatment with either of the 5-HT uptake inhibitors alaproclate (20 mg/kg) or fluoxetine (10 mg/kg). Taking into account that the noradrenergic uptake inhibitor desipramine in previous experiments failed to interfere with the effect of PCA, these results demonstrate that PCA selectively acts on 5-HT terminals. The analgesia was attenuated by administration of the 5-HT antagonists methiothepin (0.125-0.5 mg/kg) and danitracen (0.25-2.5 mg/kg) but not by a series of other 5-HT receptor antagonists or antagonists acting on noradrenergic, dopaminergic, GABAergic, histaminergic or muscarinic receptors. It is concluded that the analgesic effect of PCA is mediated via stimulation of a type of 5-HT receptors possibly belonging to the 5-HT-1 class. Further studies are, however, needed in order to firmly establish the relationship to any particular sub-type of 5-HT receptor as characterized in in vitro binding studies.

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A conformational study of R-alaproclate, a new selecetive inhibitor of neuronal 5-hydroxytryptamine uptake

Cited by 8 publications

References 5 publications

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

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

ChemInform Abstract: A CONFORMATIONAL STUDY OF R‐ALAPROCLATE, A NEW SELECTIVE INHIBITOR OF NEURONAL 5‐HYDROXYTRYPTAMINE UPTAKE

Evidence for selective serotonergic receptor involvement in p-chloroamphetamine-induced antinociception

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