-
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of the glycine transporter type 1 (GlyT1) leading to potentiation of the glycine site (GlyB) on the N-methyl-d-aspartate (NMDA) receptor has been proposed as a novel therapeutic approach for schizophrenia. However, sarcosine-based GlyT1 inhibitors produce undesirable side effects including compulsive walking and respiratory distress. The influence of specific biochemical properties of GlyT1 inhibitors, such as mode of inhibition and residence time, on adverse effects is unknown. Two GlyT1 inhibitors that contain a sarcosine moiety, sarcosine and ALX-5407, and two compounds that do not contain a sarcosine moiety, Roche-7 and Merck (S)-13h, were evaluated for their potency, mode of inhibition, and target residence times in vitro, and modulation of prepulse inhibition (PPI) and locomotor activity in vivo. (S)-13h and sarcosine were competitive inhibitors while ALX-5407 and Roche-7 demonstrated mixed noncompetitive inhibition. Potency of GlyT1 inhibition (ALX-5407>(S)-13h>Roche-7≫sarcosine) did not correlate with residence time on GlyT1 (sarcosine=Roche-7≪(S)-13h<ALX-5407). ALX-5407 and (S)-13h induced compulsive walking, termed obstinate progression (OP), at doses that increased PPI in DBA/2 mice, demonstrating that OP was not a function of mode of inhibition or inhibitor chemotype. Sarcosine and Roche-7 increased PPI without inducing OP, suggesting that compounds with decreased GlyT1 residence time were efficacious without adverse effects. Direct activation of the GlyB site by d-serine did not produce OP. However, OP induced by (S)-13h was blocked by strychnine, a glycine receptor (GlyA) antagonist, suggesting that OP induced by GlyT1 inhibition was mediated by GlyA. Thus, GlyT1 inhibitors with short residence times demonstrated efficacy without mechanism-based adverse effects.
Biochemical pharmacology 11/2010; 80(9):1407-17. · 4.25 Impact Factor
-
Joanne R Mathiasen, Beth Ann W McKenna,
Michael S Saporito,
Ghanashyam D Ghadge,
Raymond P Roos,
Beverly P Holskin,
Zhi-Liang Wu,
Stephen P Trusko,
Thomas C Connors,
Anna C Maroney,
Beth Ann Thomas,
Jeffrey C Thomas,
Donna Bozyczko-Coyne
[show abstract]
[hide abstract]
ABSTRACT: The neuropathology of Parkinson's Disease has been modeled in experimental animals following MPTP treatment and in dopaminergic cells in culture treated with the MPTP neurotoxic metabolite, MPP(+). MPTP through MPP(+) activates the stress-activated c-Jun N-terminal kinase (JNK) pathway in mice and SH-SY5Y neuroblastoma cells. Recently, it was demonstrated that CEP-1347/KT7515 attenuated MPTP-induced nigrostriatal dopaminergic neuron degeneration in mice, as well as MPTP-induced JNK phosphorylation. Presumably, CEP-1347 acts through inhibition of at least one upstream kinase within the mixed lineage kinase (MLK) family since it has been shown to inhibit MLK 1, 2 and 3 in vitro. Activation of the MLK family leads to JNK activation. In this study, the potential role of MLK and the JNK pathway was examined in MPP(+)-induced cell death of differentiated SH-SY5Y cells using CEP-1347 as a pharmacological probe and dominant negative adenoviral constructs to MLKs. CEP-1347 inhibited MPP(+)-induced cell death and the morphological features of apoptosis. CEP-1347 also prevented MPP(+)-induced JNK activation in SH-SY5Y cells. Endogenous MLK 3 expression was demonstrated in SH-SY5Y cells through protein levels and RT-PCR. Adenoviral infection of SH-SY5Y cells with a dominant negative MLK 3 construct attenuated the MPP(+)-mediated increase in activated JNK levels and inhibited neuronal death following MPP(+) addition compared to cultures infected with a control construct. Adenoviral dominant negative constructs of two other MLK family members (MLK 2 and DLK) did not protect against MPP(+)-induced cell death. These studies show that inhibition of the MLK 3/JNK pathway attenuates MPP(+)-mediated SH-SY5Y cell death in culture and supports the mechanism of action of CEP-1347 as an MLK family inhibitor.
Brain Research 05/2004; 1003(1-2):86-97. · 2.73 Impact Factor
-
Chikara Murakata,
Masami Kaneko,
George Gessner,
Thelma S Angeles,
Mark A Ator,
Teresa M O'Kane, Beth Ann W McKenna,
Beth Ann Thomas,
Joanne R Mathiasen,
Michael S Saporito,
Donna Bozyczko-Coyne,
Robert L Hudkins
[show abstract]
[hide abstract]
ABSTRACT: The MLK1-3 activity for a series of analogues of the indolocarbazole K-252a is reported. Addition of 3,9-bis-alkylthiomethyl groups to K-252a results in potent and selective MLK inhibitors. The in vitro and in vivo survival promoting activity of bis-isopropylthiomethyl-K-252a (16, CEP-11004/KT-8138) is reported.
Bioorganic & Medicinal Chemistry Letters 02/2002; 12(2):147-50. · 2.55 Impact Factor
