Synthesis and sar study of 2-substituted imidazo[2,1-b] [1,3]benzothiazoles and related compounds endowed with affinity for dopamine d2 receptors as potential antipsychotics

Schizophrenia is a complex disorder affecting approximately 1% of the population. Typical antipsychotic agents such as chlorpromazine and haloperidol block the D2 subtype of dopamine receptors in a direct relation to their clinical potency. However, although blockade of D2 receptors improves the positive symptoms of the disease, it also accounts for side effects which strongly limit patient compliance, in particular extrapyramidal effects and hyperprolactinemia. During the past few years, a second generation of antipsychotic agents has emerged (e.g.,clozapine, risperidone, olanzapine, and ziprasidone); they are categorized as atypical in contrast to conventional D2 blockers and exhibit a dual dopaminergic and serotonergic mechanism of action: a relatively weak dopamine D2 receptor antagonism in vitro and in vivo, but potentially important activities at other dopaminergic (D1, D4) receptors, at serotonergic (5-HT1A, 5HT2A, 5HT3, 5HT2C), adrenergic (a1, a2), histaminergic (H1), and muscarinic receptors. They are claimed to be active against both positive and negative symptoms of schizophrenia, even though they do exhibit a variety of other side effects as weight gain, postural hypotension, sedation, dry mouth. For these reasons the search for more effective and less toxic agents still continues [1,2]. In this context we have developed a series of (1,2-diphenyl-imidazolyl)piperazine derivatives (1) that are endowed with substantial affinities for both dopamine D2 receptors as well as 5-HT1A and 5-HT2A serotonin receptors, compound 1a (R = o-OCH3) of which is representative [3]. We have extended our study on other series of compounds derived from 1 both modifying the 1,2-diphenyl motif attached to the imidazole core, and the phenyl-piperazine moiety. All novel compounds were submitted by Lundbeck to radioligand binding assay on dopamine, serotonin, adrenergic, histaminergic receptor subtypes. The chemistry and the in vitro screening will be discussed in the poster

IMMUNOHISTOCHEMICAL EXPRESSION OF COX-2, MPGES-1 AND EP2 RECEPTOR IN HEALTHY AND REACTIVE CANINE BONE AND IN OSTEOSARCOMAS

Introduction: Accumulating evidence suggests that cyclooxygenase-2 (COX-2) is involved in growth, progression and metastasis of human osteosarcomas (OSs) and that its expression correlates with a poorer prognosis. The aim of this report was to study the expression of COX-2 in healthy, reactive, and neoplastic canine bone and to investigate the events downstream to COX-2 that lead to PGE2 production by the evaluation of mPGES-1 and EP2 receptor expression. Materials and Methods: COX-2, mPGES-1 and EP2 receptor expression were assessed by immunohistochemistry in 12 samples of normal bone, 14 reactive bones and 27 appendicular OSs. The streptavidin-peroxidase method was used. The results were quantified according to previously described scores. Results: In healthy tissues no immunoreactivity to COX-2, mPGES-1 and EP2 receptor was observed. Fifty percent of reactive bone samples scored positive for COX-2 and 57% for mPGES-1 and EP2 receptor, although with a weak labelling intensity. Ninety-three percent of OSs expressed COX-2; mPGES-1 was expressed in 85% and EP2 receptor in 89% of tumours

Immunohistochemical expression of COX-2, mPGES and EP2 receptor in normal and reactive canine bone and in canine osteosarcoma

Accumulating evidence suggests that cyclooxygenase (COX)-2 is involved in the pathogenesis of human and canine osteosarcoma. The aim of this study was to investigate the expression of COX-2 in normal, reactive and neoplastic canine bone and the events downstream to COX-2 that lead to prostaglandin E2 (PGE2) production. COX-2, microsomal PGE2 synthase-1 (mPGES-1) and the PGE2 receptor (EP2) were assessed by immunohistochemistry in 12 samples of normal bone, 14 cases of fracture callus and 27 appendicular osteosarcomas. No immunoreactivity to COX-2, mPGES-1 or EP2 receptor was observed in normal bone. Fifty percent of reactive bone samples expressed COX-2 and 57% expressed mPGES-1 and EP2 receptor, although with weak labelling intensity. Ninety-three percent of osteosarcomas expressed COX-2, while mPGES-1 was expressed by 85% and EP2 receptor by 89% of the tumours. The data confirm that COX-2 is expressed at high level in osteosarcoma and support the use of COX-2 inhibitors to improve the response to chemotherapy. The possibility of blocking the EP2 or the selective inhibition of mPGES-1, rather than COX-2 activity, might decrease the incidence of adverse effects that occur due to the inhibition of prostanoids other than PGE2

Immunohistochemical Expression of COX-2, mPGES and EP2 Receptor in Normal and Reactive Canine Bone and in Canine Osteosarcoma.

Accumulating evidence suggests that cyclooxygenase (COX)-2 is involved in the pathogenesis of human and canine osteosarcoma. The aim of this study was to investigate the expression of COX-2 in normal, reactive and neoplastic canine bone and the events downstream to COX-2 that lead to prostaglandin E2 (PGE2) production. COX-2, microsomal PGE2 synthase-1 (mPGES-1) and the PGE2 receptor (EP2) were assessed by immunohistochemistry in 12 samples of normal bone, 14 cases of fracture callus and 27 appendicular osteosarcomas. No immunoreactivity to COX-2, mPGES-1 or EP2 receptor was observed in normal bone. Fifty percent of reactive bone samples expressed COX-2 and 57% expressed mPGES-1 and EP2 receptor, although with weak labelling intensity. Ninety-three percent of osteosarcomas expressed COX-2, while mPGES-1 was expressed by 85% and EP2 receptor by 89% of the tumours. The data confirm that COX-2 is expressed at high level in osteosarcoma and support the use of COX-2 inhibitors to improve the response to chemotherapy. The possibility of blocking the EP2 or the selective inhibition of mPGES-1, rather than COX-2 activity, might decrease the incidence of adverse effects that occur due to the inhibition of prostanoids other than PGE2

Immunohistochemical Expression of COX-2, mPGES and EP2 Receptor in Normal and Reactive Canine Bone and in Canine Osteosarcoma

Accumulating evidence suggests that cyclooxygenase (COX)-2 is involved in the pathogenesis of human and canine osteosarcoma. The aim of this study was to investigate the expression of COX-2 in normal, reactive and neoplastic canine bone and the events downstream to COX-2 that lead to prostaglandin E2(PGE2) production. COX-2, microsomal PGE2synthase-1 (mPGES-1) and the PGE2receptor (EP2) were assessed by immunohistochemistry in 12 samples of normal bone, 14 cases of fracture callus and 27 appendicular osteosarcomas. No immunoreactivity to COX-2, mPGES-1 or EP2 receptor was observed in normal bone. Fifty percent of reactive bone samples expressed COX-2 and 57% expressed mPGES-1 and EP2 receptor, although with weak labelling intensity. Ninety-three percent of osteosarcomas expressed COX-2, while mPGES-1 was expressed by 85% and EP2 receptor by 89% of the tumours. The data confirm that COX-2 is expressed at high level in osteosarcoma and support the use of COX-2 inhibitors to improve the response to chemotherapy. The possibility of blocking the EP2 or the selective inhibition of mPGES-1, rather than COX-2 activity, might decrease the incidence of adverse effects that occur due to the inhibition of prostanoids other than PGE2. \ua9 2012 Elsevier Ltd

Molecular phenotype in mammary tumors of queens: correlation between primary tumor and lymph node metastasis

The molecular characterization of mammary tumours represents a new stage in the development of effective predictive models and targeted therapies. The aim of this study was to evaluate the relationship between the molecular phenotype of a primary feline mammary tumour and that of a related lymph node metastasis. Twenty-one mammary tumour samples and their lymph node metastases were selected and evaluated immunohistochemically for expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (c-erbB-2), cytokeratin 5/6, cytokeratin 14, cytokeratin 19 and protein 63. Mammary tumours were classified into five subtypes: luminal A, luminal B, c-erbB-2 overexpressing, basal-like and normal-like, based on an algorithm applied in both human and veterinary medicine. Concordance between the primary tumour and its lymph node metastasis was detected in 12 of 21 cases (57.1%). In the remaining nine cases (42.9%) there was discordance in the molecular profile at the two sites. Therefore, the tumour molecular profile must be evaluated in both sites in order to obtain definitive identification of the tumour profile (or profiles) and to plan an appropriate therapy