Synthesis and preliminary pharmacological evaluation of trans-2-amino-5(6)-chloro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes as dopamine receptor ligands

A series of trans-2-amino-5(6)-chloro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes were synthesized and evaluated for their binding affinity toward D-1-like and D-2-like dopamine (DA) receptors. The affinity and selectivity of these compounds were measured in a test involving displacement of [H-3]SCH 23390 or [H-3]YM-09-151-2, respectively, from homogenates of porcine striatal membranes. All tested compounds were poorly effective at DA receptors (K-i nM > 1000). The results suggest that introduction of chlorine substituent in five or six position of previously synthesized trans-2-amino-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes decreases both D-1-like and D-2-like receptor affinity. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved

Synthesis and preliminary pharmacological evaluation of 5-hydroxy-and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo [5,6]cycloheptal [1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands

A series of 5-hydroxy- and 5,6-dihydroxy- 1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-iJ]isoquinoline derivatives (5a-e and 6a-e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D-1 and D-2 dopamine receptors. All compounds showed lower D1 and D affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij] 5a and the 5,6dihydroxy analogue 6a showed D-2 agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D-1 and D-2 selective ligands. (C) 2001 Elsevier Science Ltd. All rights reserved

Risk of neuroblastoma, maternal characteristics and perinatal exposures: The SETIL study.

Neuroblastoma (NB) is the most common extra-cranial paediatric solid tumour. Incidence peaks in infancy, suggesting a role of in-utero and neonatal exposures but its aetiology is largely unknown. The aim of the present study is to evaluate the association between maternal characteristics and perinatal factors with the risk of NB, using data from the SETIL database.SETIL is a large Italian population-based case-control study established to evaluate several potential cancer risk factors in 0-10 year olds. Information about maternal characteristics, reproductive history, environmental and occupational exposures during pregnancy, as well as newborns' characteristics were obtained using a structured questionnaire. Extremely low frequency magnetic field (ELF-MF) home exposure was measured. The study included 1044 healthy controls and 153 NB cases, diagnosed between 1998 and 2001.A twofold risk was associated to exposure in pregnancy to chemical products for domestic work and to hair dye. The risk associated with the latter was higher among 0-17 month old children (OR=5.5, 95\%CI: 1.0-29.3). Risk was increased for children whose mothers had suffered work related exposure in the preconception period to solvents (OR=2.0 95\%CI: 1.0-4.1) and in particular to aromatic hydrocarbons (OR=9.2, 95\%CI: 2.4-34.3). No association was observed with ELF-MF exposure. A higher risk was found among children with congenital malformations (OR=4.9, 95\%CI: 1.8-13.6) or neurofibromatosis (2 cases and 0 controls, p=0.016).Our study suggests maternal exposure to hair dyes and aromatic hydrocarbons plays a role and deserves further investigation. The association with congenital malformations might also be explained by over-diagnosis. External exposure, in particular during and before pregnancy might contribute to NB occurrence

Childhood cancer survival in Europe.

BACKGROUND: EUROCARE-3 collected data from 45 population-based cancer registries in 20 countries on 24 620 European children aged from 0 to 14 years diagnosed with malignancy in the period 1990-1994. METHODS: Five-year survival between countries was compared for all malignancies and for the major diagnostic categories, adjusting for age, and estimated average European survival weighting for differences in childhood populations. RESULTS: For all cancers combined, survival variation was large (45% in Estonia to 90% in Iceland), and was generally low (60-70%) in eastern Europe and high (> or =75%) in Switzerland, Germany and the Nordic countries (except Denmark). The Nordic countries had the highest survival for four of the seven major tumour types: nephroblastoma (92%), acute lymphoid leukaemia (85%), CNS tumours (73%) and acute non-lymphocytic leukaemia (62%). The eastern countries had lowest survival: 89% for Hodgkin's disease, 71% for nephroblastoma, 68% for acute lymphoid leukaemia, 61% for non-Hodgkin's lymphoma, 57% for central nervous system (CNS) tumours and 29% for acute non-lymphocytic leukaemia. CONCLUSIONS: The Nordic countries represent a survival gold standard to which other countries can aspire. Since most childhood cancers respond well to treatment, survival differences are attributable to differences in access (including referral and timely diagnosis) and use of modern treatments; however, the obstacles to access and application of standard treatments probably vary markedly with country