ABSTRACT
The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Neuralgia/drug therapy , Piperidines/pharmacology , Receptors, sigma/metabolism , Adamantane/chemical synthesis , Adamantane/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Caspase 3/metabolism , Cell Cycle/drug effects , Female , Humans , Male , Mice , Mice, SCID , Molecular Structure , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Piperidines/chemical synthesis , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protein Binding , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.
Subject(s)
Adamantane/chemistry , Adamantane/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Receptors, sigma/chemistry , Adamantane/chemical synthesis , Adamantane/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Female , Humans , Male , Mice , Mice, SCID , Neoplasms/drug therapyABSTRACT
The nitric oxide free radical (NO(*)), which is synthesized by neuronal nitric oxide synthase (nNOS), is known to play an important morphogenetic role in the developing rat brain. In the cortex, the levels of nNOS are regulated by phosphorylated cAMP response element binding protein (pCREB) downstream of GABA-A receptor activation. During early stages of neonatal development, binding of GABA to its type A receptors leads to depolarization of the neuronal membrane. One of the developmental processes mediated through GABA-A receptors is the sexual differentiation of the brain. In the present work, we investigated the effect of GABA-A receptor activation on nNOS and pCREB immunoreactivity in the developing diencephalon of 5-day-old male and female rats. Our results showed that in the bed nucleus of the stria terminalis activation of GABA-A receptors leads to increased numbers of nNOS, and pCREB as well as nNOS-pCREB doubly immunopositive cells only in the males while in the posterior hypothalamus this effect is observed in both sexes. The GABA-A receptor-mediated increase in nNOS and pCREB is abolished when L-type voltage-gated Ca(2+) channels are blocked. These results indicate that the following mechanism could be operating in a gonadal hormone-dependent and brain area-specific manner during neonatal rat brain development: Depolarization following GABA-A receptor activation leads to opening of L-type voltage-gated calcium channels, resulting in an increased Ca(2+) influx, which in turn leads to phosphorylation, and thus activation of the transcription factor CREB; the phosphorylated CREB can then induce nNOS.
Subject(s)
Diencephalon/growth & development , Diencephalon/metabolism , Nitric Oxide Synthase Type I/metabolism , Receptors, GABA-A/metabolism , Animals , Animals, Newborn , Cyclic AMP Response Element-Binding Protein/metabolism , Female , Image Processing, Computer-Assisted , Immunohistochemistry , Male , Rats , Rats, Wistar , Sex CharacteristicsABSTRACT
Early experiences have long-term effects on brain function and behavior. However, the precise mechanisms involved still remain elusive. In an effort to address this issue, we employed the model of "early handling", which is known to affect the ability of the adult organism to respond to stressful stimuli, and determined its effects on hippocampal pCREB and BDNF 2, 4, and 8 h later. 8 h following "handling" on postnatal day 1, there was an increase in pCREB and BDNF positive cells in the hippocampus, a brain area which is a specific target of "handling". On the other hand, vehicle injection resulted in decreased pCREB and BDNF in both handled and non-handled animals 2 and 4 h later. The "handling"-induced increase of pCREB and BDNF was cancelled by inhibition of NMDA, AMPA/kainate, GABA-A, 5-HT1A or 5-HT2A/C receptors, as well as L-type voltage-gated Ca(2+) channels. It thus appears that "early handling" activates these neurotransmitter receptors, leading to increased intracellular Ca(2+), phosphorylation of the transcription factor CREB, and increased BDNF expression. BDNF can then exert its morphogenetic effects and thus "imprint" the effects of "handling" on the brain.
