Delving into the Latest Updates on AMT-2003 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AMT

Target-

Action

stimulants

Mechanism

Immunostimulants

Therapeutic Areas

NeoplasmsDigestive System DisordersUrogenital Diseases

Active Indication-

Inactive Indication

Advanced cancerAdvanced Colorectal AdenocarcinomaAdvanced Hepatocellular Carcinoma+ [3]

Originator Organization

Auron Healthcare GmbH

Active Organization-

Inactive Organization

Auron Healthcare GmbH

License Organization-

Drug Highest PhaseDiscontinuedPhase 2/3

First Approval Date-

Regulation-

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Abstract Newly synthesized allyloxymethyl purine and pyrimidine acyclonucleosides [Fig. 1, comp. 1-6] were tested in Syrian hamster, six days after heterotransplantations of Kirkman-Robbins hepatoma and compared with Th5, Th5P and PMT [Fig. 1, comp. 7 -9 ]. 48 hours after intraperitoneal (i.p.) administration of AMT and Th5 in a dose of 80 mg per kg body weight, these compounds reduced tumor weight by 42%, while AMU (in the same dose) by 30%. The inhibition of tumor weight is accompanied by a decrease in dThd and dGuo kinase activities in tumor cytosol by AMU (36% and 33%, respectively) by AM T (59% and 53%, respectively) and by Th5 (58% and 55%, respectively). AMU, AMT and Th5 are phosphorylated in vivo by kinases present in cytosol of growing hepatom a to mono, di and triphosphates, but allyloxymethyl residue of AMU and AMT is first hydrated to hydroxypropoxymethyl residue, having CH2OH group. The lack of phosphorylation of PMT in vivo (having saturated propoxymethyl residue) and phosphorylation of Th5P (when used as a substrate for dNMP kinase) only to Th5 diphosphate suggested that AMU, AM T and Th5 triphosphates are responsible for the inhibition of dTMP and dGMP synthesis.

01 Jan 1983·Australian Journal of Biological Sciences

Different Acute Effects of the Tyrosine Hydroxylase Inhibitors a-Methyl-p-Tyrosine and 3-Iodo-L-Tyrosine on Hypothalamic Noradrenaline Activity and Adrenocorticotrophin Release in the Rat

Article

Author: Bradshaw, J. E. ; Smythe, G. A.

Computerized gas chromatography-mass spectrometry techniques using selected ion monitoring and deuterated internal standards were used to assay simultaneously the medial basal hypothalamic concentrations of dopamine (DA) and noradrenaline (NA) and their major metabolites in individual rats 30 min after the administration of two different inhibitors of tyrosine hydroxylase, a-methyl-ptyrosine (a-MT) and 3-iodo-L-tyrosine (MIT). Consistent with inhibition of DA synthesis, administration of both a-MT and MIT resulted in marked reductions (P<O� 005) in the hypothalamic concentrations of DA and its metabolite homovanillic acid as well as in highly significant increases in prolactin secretion. a-MT administration, but not MIT, resulted in a highly significant decrease in NA concentration and a highly significant increase in the concentration of the NA metabolite 3,4- dihydroxyphenylethyleneglycol (DHPG). The hypothalamic ratio DHPG/NA was thus markedly increased (P<O� 005) by a-MT indicating increased NA neuronal activity. a-MT administration also resulted in increased ACTH secretion (P<O� 0005), an effect not observed following MIT

Basic and Clinical Neuroscience Journal

The Influence of Striatal Astrocyte Dysfunction on Locomotor Activity in Dopamine-depleted Rats

Article

Author: Guschina, Anastasia ; Illarioshkin, Sergey ; Voronkov, Dmitry ; Stavrovskaya, Alla ; Khudoerkov, Rudolf ; Olshanskiy, Artyom

Introduction: Astrocyte dysfunction is the common pathology failing astrocyte-neuron interaction in neurological diseases, including Parkinson’s Disease (PD). The present study aimed to evaluate the impacts of astrocytic dysfunction caused by striatal injections of selective glial toxin L-Aminoadipic Acid (L-AA) on the rats’ locomotor activity in normal conditions and under alpha-methyl-p-tyrosine depletion of catecholamines synthesis. Methods: Thirty-three male Wistar rats were used in the experiments. Intrastriatal L-AA injections (100 µg) were performed into the right striatum. Alpha-methyl-p-tyrosine (a-MT, 100 mg/kg, inhibitor of tyrosine hydroxylase) was intraperitoneally injected for catecholamine depletion. The animals were divided into 5 groups, as follows: 1. L-AA treated (n=7), 2. L-AA+a-MT treated (n=5), 3. Sham-operated (n=7), 4. Sham+a-MT treated (n=5), 5. Intact control (n=9). For assessing motor function, open field and beam walking tests were used on the third day after the operation. Neuronal and astrocyte markers (glial fibrillary acidic protein, glutamine synthetase, tyrosine hydroxylase, & neuronal nuclear antigen) were examined in the striatum by immunohistochemistry. Results: Administrating L-AA led to astrocytic degeneration in the striatum. No neuronal death and disruption of dopaminergic terminals were detected. L-AA and a-MT-treated animals’ distance traveled was significantly (P=0.047) shorter than the Sham-operated group injected with a-MT. In the walking beam test, the number of unilateral paw slippings was significantly (P<0.01) higher in the L-AA-treated group than Sham-operated animals. Administrating a-MT alone and L-AA did not change rats’ performance in walking beam tests. Conclusion: Astrocyte ablation in dopamine depleted striatum resulted in reduced motor activity and asymmetrical gait disturbances. These findings demonstrated the role of astroglia in motor function regulation in the nigrostriatal system and suggest the possible association of glial dysfunction with motor dysfunction in PD.

100 Deals associated with AMT-2003

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Hepatocellular Carcinoma	Phase 3	Germany	Auron Healthcare GmbH	01 Mar 2007
Advanced Colorectal Adenocarcinoma	Phase 3	Germany	Auron Healthcare GmbH	01 Oct 2006
Advanced cancer	Phase 3	Germany	Auron Healthcare GmbH	01 May 2006
Advanced cancer	Phase 3	Bosnia and Herzegovina	Auron Healthcare GmbH	01 May 2006
Female Genital Neoplasms	Phase 3	Bosnia and Herzegovina	Auron Healthcare GmbH	01 May 2006
Female Genital Neoplasms	Phase 3	Germany	Auron Healthcare GmbH	01 May 2006
Gastrointestinal Neoplasms	Phase 3	Bosnia and Herzegovina	Auron Healthcare GmbH	01 May 2006
Prostatic Cancer	Phase 3	Bosnia and Herzegovina	Auron Healthcare GmbH	01 May 2006
Prostatic Cancer	Phase 3	Germany	Auron Healthcare GmbH	01 May 2006