Discovery of Selective Cannabinoid CB Receptor Agonists by High-Throughput Screening.

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB and CB) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB that are enriched in the CNS. CB, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB activation.

Design of an automated enhanced-throughput platform for functional characterization of positive allosteric modulator-induced leftward shifts in apparent agonist potency in vitro.

Prosecution of positive allosteric modulator (PAM) targets demands a specialized assay toolset. Many GPCR or ion channel targets are adaptable to functional assays whereby PAM efficacy can be inferred from left or rightward shifts in the concentration-response curves of orthosteric agonist. The inherent emphasis on throughput and occasional paucity of radioligands for a diverse array of allosteric modulator targets yields a need for an enhanced throughput agonist potency shift assay.

HTS in the new millennium: the role of pharmacology and flexibility.

Over the past decade, high throughput screening (HTS) has become the focal point for discovery programs within the pharmaceutical industry. The role of this discipline has been and remains the rapid and efficient identification of lead chemical matter within chemical libraries for therapeutics development. Recent advances in molecular and computational biology, i.

A mitochondrial bottleneck hypothesis of Alzheimer's disease.

Alzheimer's disease, in its early onset familial form, is known to be a heterogeneous disorder. This suggests that the different degenerative mechanisms, initiated by different genetic causes and ending in the shared phenotype of the disease, should intersect at some point in the degenerative cascade to form a 'bottleneck' from which the pathological features that are common to each of the genetic forms emerge. A growing body of evidence suggests that disturbances of energy metabolism may play a fundamental role in the onset and progression of Alzheimer's disease.

A new glibenclamide-insensitive neuroselective hyperpolarizing agent.

We describe a novel compound, (-)-N-(2-ethoxyphenyl)-N'-(1,2,3-trimethylpropyl)-2-nitroethene-1, 1-diamine), Bay x9227, that demonstrates dose-dependent hyperpolarizing activity of remarkable potency (EC50 3 picomolar) and selectivity for CNS neurons and clonal neurotypic cells compared to smooth muscle cells. Single cell membrane potential measurements were obtained in physiologic buffer using the fluorescent probe, bisoxonol. Unlike K+ATP-channel activators including its (+)-enantiomer (Hoffman et al.