Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca(2+)-activated K+ channels.

Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca(2+)-activated K(+) ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further.

The slow afterhyperpolarization: a target of β1-adrenergic signaling in hippocampus-dependent memory retrieval.

In rodents, adrenergic signaling by norepinephrine (NE) in the hippocampus is required for the retrieval of intermediate-term memory. NE promotes retrieval via the stimulation of β1-adrenergic receptors, the production of cAMP, and the activation of both protein kinase A (PKA) and the exchange protein activated by cAMP. However, a final effector for this signaling pathway has not been identified.

Personal reflections on Sir James Black (1924-2010) and histamine.

Sir James Black, Nobel laureate (1988), became interested in the role of histamine in gastric acid secretion in the early 1950s. In 1964, he joined the pharmaceutical company Smith Kline and French Laboratories at their English subsidiary to seek a new type of antagonist that would block those actions of histamine that were not blocked by mepyramine. No such compound was known and working with medicinal chemists it took four years to discover a lead compound.

Refined docking as a valuable tool for lead optimization: application to histamine H3 receptor antagonists.

Drug-discovery projects frequently employ structure-based information through protein modeling and ligand docking, and there is a plethora of reports relating successful use of them in virtual screening. Hit/lead optimization, which represents the next step and the longest for the medicinal chemist, is very rarely considered. This is not surprising because lead optimization is a much more complex task.