Development of Potent Adenosine Monophosphate Activated Protein Kinase (AMPK) Activators

Previously, we reported the identification of a thiazolidinedione‐based adenosine monophosphate activated protein kinase (AMPK) activator, compound 1 (N‐[4‐({3‐[(1‐methylcyclohexyl)methyl]‐2,4‐dioxothiazolidin‐5‐ylidene}methyl)phenyl]‐4‐nitro‐3‐(trifluoromethyl)benzenesulfonamide), which provided a proof of concept to delineate the intricate role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial–mesenchymal transition (EMT) in cancer cells. In this study, we used 1 as a scaffold to conduct lead optimization, which generated a series of derivatives. Analysis of the antiproliferative and AMPK‐activating activities of individual derivatives revealed a distinct structure–activity relationship and identified 59 (N‐(3‐nitrophenyl)‐N′‐{4‐[(3‐{[3,5‐bis(trifluoromethyl)phenyl]methyl}‐2,4‐dioxothiazolidin‐5‐ylidene)methyl]phenyl}urea) as the optimal agent. Relative to 1 , compound 59 exhibits multifold higher potency in upregulating AMPK phosphorylation in various cell lines irrespective of their liver kinase B1 (LKB1) functional status, accompanied by parallel changes in the phosphorylation/expression levels of p70S6K, Akt, Foxo3a, and EMT‐associated markers. Consistent with its predicted activity against tumors with activated Akt status, orally administered 59 was efficacious in suppressing the growth of phosphatase and tensin homologue (PTEN)‐null PC‐3 xenograft tumors in nude mice. Together, these findings suggest that 59 has clinical value in therapeutic strategies for PTEN‐negative cancer and warrants continued investigation in this regard.     

Effect of cholinesterase inhibitors on Morris water task behavior following lesions of the nucleus basalis magnocellularis.

The effect of bilateral nucleus basalis magnocellularis (nBM) lesions on performance in the Morris water task was examined in the rat, and the ability of anticholinesterase inhibitors to reverse the behavioral deficit was evaluated. Lesions of nBM resulted in a prolongation of escape latency. A spatial probe trial revealed that sham-lesioned Ss swam a greater percentage of the distance in the platform quadrant; this finding was abolished by nBM lesions. Lesions of nBM produced a nonsignificant increase in both open-field activity and activity-box scores. In Exp 1, administration of physostigmine on Day 3 resulted only in a decrease in escape latency. In Exp 2, in which cholinesterase inhibitors were administered daily for 5 days, 0.32 mg/kg but not low-dose physostigmine or 2 substituted N,N-alkyl phenyl carbamate cholinesterase inhibitors improved escape latency on Day 3. It is concluded that nBM lesions impair behavior on the Morris water task and physostigmine shortens escape latency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nucleus basalis magnocellularis lesions: Lack of biochemical and immunocytochemical recovery and effect of cholinesterase inhibitors on passive avoidance.

[Correction Notice: An erratum for this article was reported in Vol 103(1) of Behavioral Neuroscience (see record 2008-10623-003). The plate for this article appears on page 997. The information should read, "Plate C. Choline acetyltransferase (CAT) immunoreactivity at 1 week and 3 months following unilateral ibotenic acid nucleus basalis magnocellularis (NBM) lesion."] Lesions of the rat nucleus basalis magnocellularis (nBM) result in a marked decrease in cortical choline acetyltransferase (CAT) and in behavioral deficits. After unilateral ibotenic acid lesions of the nBM in rats, there was significant ipsilateral loss of frontal and parietal CAT, which did not recover for 3 mo and was accompanied by a loss of CAT immunoreactivity in the peripallidal region. Bilateral ibotenate nBM lesions resulted in a marked deficit of 1-trial step-through passive avoidance (PA) at 24 hrs. Cholinesterase inhibitors including physostigmine, N-ethylalkylphenyl carbamate (RA-6), and N,N-methylethylphenyl carbamate were administered in separate experiments, for 2 days before retrieval testing or for 3 consecutive days during consolidation immediately following training. Nonsignificant improvements in PA latency were produced using physostigmine and RA-6 administered before retrieval testing. Results suggest that destruction of cholinergic neurons in the nBM is involved in the PA deficit, but does not exclude the possibility that damage to other systems may contribute to the behavioral deficit. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

"Nucleus basalis magnocellularis lesions: Lack of biochemical and immunocytochemical recovery and effect of cholinesterase inhibitors on passive avoidance": Correction.

Reports an error in "Nucleus basalis magnocellularis lesions: Lack of biochemical and immunocytochemical recovery and effect of cholinesterase inhibitors on passive avoidance" by Leon J. Thal, Carl P. Dokla and David M. Armstrong (Behavioral Neuroscience, 1988[Dec], Vol 102[6], 852-860). The plate for this article appears on page 997. The information should read, "Plate C. Choline acetyltransferase (CAT) immunoreactivity at 1 week and 3 months following unilateral ibotenic acid nucleus basalis magnocellularis (NBM) lesion." (The following abstract of the original article appeared in record 1989-28786-001.) Lesions of the rat nucleus basalis magnocellularis (nBM) result in a marked decrease in cortical choline acetyltransferase (CAT) and in behavioral deficits. After unilateral ibotenic acid lesions of the nBM in rats, there was significant ipsilateral loss of frontal and parietal CAT, which did not recover for 3 mo and was accompanied by a loss of CAT immunoreactivity in the peripallidal region. Bilateral ibotenate nBM lesions resulted in a marked deficit of 1-trial step-through passive avoidance (PA) at 24 hrs. Cholinesterase inhibitors including physostigmine, N-ethylalkylphenyl carbamate (RA-6), and N,N-methylethylphenyl carbamate were administered in separate experiments, for 2 days before retrieval testing or for 3 consecutive days during consolidation immediately following training. Nonsignificant improvements in PA latency were produced using physostigmine and RA-6 administered before retrieval testing. Results suggest that destruction of cholinergic neurons in the nBM is involved in the PA deficit, but does not exclude the possibility that damage to other systems may contribute to the behavioral deficit. (PsycINFO Database Record (c) 2011 APA, all rights reserved)