LY 2389575 hydrochloride

LY2389575 is described here instead of LY2389575 hydrochloride. LY2389575 is a selective negative allosteric modulator (NAM) of metabotropic glutamate receptor 3 (mGlu3) with an IC50 value of 4.2 μM [1].

The metabotropic glutamate receptors (mGlus) are members of the GPCR family C. They are characterized by a large extracellular amino-terminal domain for binding agonist. Eight mGlus had been found and were assigned to three groups based on their pharmacology, sequence homology, and mechanisms to couple to effector. They are Group I: mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III: mGlu4,6,7,8 [1].

In mixed neuronal cultures, LY2389575 abolished the protective activity of 1 μM LY379268 (the orthosteric mGlu2/3 receptor agonist) in the concentration range of 0.1 to 1 μM and amplified Aβ toxicity on its own at the highest concentration. In the absence of Aβ, LY2389575 at these concentrations was not toxic (numbers of dead neurons in control cultures and in cultures treated with 1 μM LY2389575 were 41 ± 3, and 42 ± 1, respectively). Further data indicated that LY2389575 was able to amplify Aβ toxicity and abolish the neuroprotective activity of LY379268 only in cultures containing wild-type astrocytes. In the FLIPR assay system, LY2389575 behaved as a noncompetitive mGlu3 receptor antagonist with an efficacy of 100 ± 0.68% and an IC50 value of 190 ± 26 nM. LY2389575 failed in affecting responses mediated by all other mGlu receptor subtypes or GABAB receptors [2].

No in vivo data for the application of this drug had been found.

References:
[1].  Sheffler DJ, Wenthur CJ, Bruner JA, et al. Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM[J]. Bioorganic & medicinal chemistry letters, 2012, 22(12): 3921-3925.
[2].  Caraci F, Molinaro G, Battaglia G, et al. Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective[J]. Molecular pharmacology, 2011, 79(3): 618-626.

[Phase I study of gemcitabine hydrochloride (LY 188011) combination therapy with cisplatin in the patients with non-small cell lung cancer].[Pubmed:10396316]

Gan To Kagaku Ryoho. 1999 Jun;26(7):898-907.

The combination Phase I study of gemcitabine hydrochloride with cisplatin was conducted in the patients with non-small cell lung cancer (NSCLC) at 5 investigation sites. Gemcitabine was administrated on day 1, 8 and 15 and cisplatin on day 1 of each 28-day cycle. The dosage of cisplatin was fixed to 80 mg/m2 and the dosage of Gemcitabine was gradually escalated in 3 dosing level from 600, 800 to 1,000 mg/m2. The maximum tolerated dose (MTD) and the recommended dose was determined with Continual Reassessment Method. For each dose level, 6 cases, 3 cases and 6 cases were registered respectively and all 15 cases were evaluable. In the dose level 3 with 1,000 mg/m2 of gemcitabine and 80 mg/m2 of cisplatin, grade 4 neutropenia was observed as DLT in 3 out of 6 cases, thus dose level 3 was considered as MTD and the recommended dose. Major adverse events were leukopenia, neutropenia, nausea/vomiting and anorexia. The incidence of such adverse events seemed to be dose-dependent and especially the grade of neutropenia seemed to be more serious as the dose increased. Also, the grade of liver function tests abnormal seemed to be more serious as the dose increased but the incidence as well as the grade did not have tendency of dose-dependent in another events including renal function tests abnormal. On the other hand, as to the efficacy PR was observed in 4 out of 15 cases. Based upon the results, it is necessary to discuss further the efficacy in the recommended dose in the combination therapy of gemcitabine and cisplatin.

[An early phase II study of gemcitabine hydrochloride (LY 188011). Gemcitabine Cooperative Study Group for Early Phase II].[Pubmed:8937492]

Gan To Kagaku Ryoho. 1996 Nov;23(13):1813-24.

An early phase II cooperative study of Gemcitabine Hydrochloride (abbreviated to "gemcitabine" herewith) was conducted in patients with a variety of solid tumors (i.e., lung cancer, gastric cancer, pancreatic cancer, colon/rectum cancer, cervical cancer, ovarian cancer and breast cancer) at 56 institutions. The aim of the first step (Step I) was to investigate the feasibility of gemcitabine in a variety of different solid tumors, including lung cancer regarding efficacy and safety. The aim of the second step (Step II) was as a result of step I (Responses were observed) to continue to investigate the efficacy and safety of gemcitabine in chemonaive patients with non-small cell lung cancer. As a Step I study, gemcitabine was administered once weekly at a dose of 800 mg/m2 for a consecutive 3-week period followed by a week of rest, in multiple courses. Among the 29 eligible patients with lung cancer, partial response (PR) was achieved in 3 patients (25.0%, 95% confidence interval: 5.5-57.2%) out of 12 chemonaive patients. Adverse reactions (grade 3 or higher) seen in 29 patients with lung cancer were neutropenia (27.6%), leukopenia (13.8%), decreased hemoglobin (13.8%), thrombocytopenia (10.3%), malaise (6.9%), anorexia (3.4%), nausea/vomiting (3.4%), diarrhea (3.4%), dyspnea (3.4%) and interstitial pneumonia (3.4%). In other types of solid tumors, PR was achieved in 2 (8.7%) out of 23 eligible patients with cervical cancer and in 1 (5.3%) of 19 eligible patients with ovarian cancer, while the use of analgesics became unnecessary in 1 patient with pancreatic cancer. Incidence as well as severity of main adverse reactions in these patients were comparable to those seen in patients with lung cancer. A Step II study, in which gemcitabine was administered once weekly at a dose of 1,000 mg/m2 to chemonaive patients with non-small cell lung cancer, was conducted, referring to the results of Step I and clinical studies conducted overseas. The results of the Step II study demonstrated PR in 5 (14.3%, 95% confidence interval: 4.8 - 30.3%) out of 35 eligible patients with non-small cell lung cancer and that the main adverse reactions were comparable to those seen in the Step I study, posing no tolerability problems in particular.

Changes in motor activities induced by microinjections of the selective dopamine agonists LY 171555, quinpirole hydrochloride, and SK&F 38393 into the habenula nucleus.[Pubmed:3495009]

Pharmacol Biochem Behav. 1987 Mar;26(3):643-6.

The effects on behaviour of microinjections into the habenula complex of selective agonists for dopamine D-1 (SK&F 38393) and D-2 (LY 171555) receptors were documented in a holeboard, open-field test. The D-2 agonist reduced grooming responses, locomotor activity and rearing behaviour. In contrast, the D-1 agonist increased rearing and locomotor activity but was without effect on grooming responses. Neither drug produced significant effects on inspective hole exploration. The data extend findings of behavioural consequences of central D-1 receptor activation and provide direct evidence in support of the functional and behavioural importance of intrahabenular dopamine receptor sites. The findings are consistent with suggestions for feedback regulation of habenular efferents to midbrain dopaminergic neurons. Effects of both receptor agonists on some responses but not others indicates potential complex interactions between D-1 and D-2 receptors within the habenula.

Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective.[Pubmed:21159998]

Mol Pharmacol. 2011 Mar;79(3):618-26.

Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic beta-amyloid protein (Abeta) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Abeta-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Abeta toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-beta1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Abeta neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Abeta toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Abeta, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Abeta-induced toxicity.