PubMed Health⌕ Search

Biomedical subjects

David J Triggle

Publications and source records attributed to David J Triggle.

8 recordsLinked to original sources
PubMed2007

Drug discovery and delivery in the 21st century.

Drug discovery in the late 20th century has increasingly focused on the definition and characterization of the macromolecular substrates that serve as targets for drug design. The advent of genomics and the molecular biology revolution has permitted both the definition of new targets and the characterization of the genetic basis of disease states. The introduction of powerful new technologies should greatly accelerate the pace of new drug discovery. Although genomics, both human and nonhuman, should in principle increase the number of potential drug targets and provide a greater understanding of cellular events contributing to the pathology of disease this has yet to occur in practice, primarily because of the underlying complexity of cellular signaling processes. The emerging discipline of systems biology is attempting to bring both order and understanding to these signaling processes. Genomics has, however, impacted on drug discovery in ways that are important beyond a mere increase in potential drug target numbers. Genomics has provided the tools of contemporary drug discovery, the pharmacogenomic pathways to personalized medicine, and has greatly influenced the nature of synthetic organic chemistry, a discipline that is still the cornerstone of contemporary drug discovery. In the future, genomics and the tools of molecular biology will have a corresponding impact on drug delivery processes and mechanisms through introduction of drug delivery machines capable of both synthesis and activation by disease-specific signals. Such machines will be based on a synthetic genome, using an expanded genetic code, and designed for specific drug synthesis and delivery and activation by a pathological signal. This essay is based upon a lecture of the same title presented at the Faculty of Medicine, Kuwait University during a visit in the spring of 2005. It is intended, as was the lecture, to be a broad, descriptive and speculative overview rather than a comprehensive and detailed review.

Drug Delivery Systems↗
PubMed2006

L-type calcium channels.

The Ca2+ channel blockers represent a successful group of therapeutic agents directed against cardiovascular targets, including hypertension and angina. These drugs, including the first-generation verapamil, nifedipine and diltiazem are directed against a subclass of voltage-gated Ca2+ channel - the L-type channel. Other subclasses of Ca2+ channel exist and are targets for new indications. The mechanisms of actions of the L-type blockers are discussed and the origins of their cardiovascular selectivity discussed. Although new drugs of this class directed against hypertension could be developed, there are both clinical and economic reasons that argue against such development. However, there are other possible targets to investigate where antagonists and activators of the L-type channel may be useful: such targets include fertility, neuronal growth, bone formation and epilepsy. Limitations to these approaches are discussed.

Animals↗
PubMed2005

Mechanism of tissue-selective drug action in the cardiovascular system.

Analysis of the human genome project tells us that there may be as few as 3000 genes that are likely to be good drug targets. Although the number of targets is still very large, these data have been interpreted by some to mean that the pharmaceutical industry may someday run out of novel drug targets. Despite the doom and gloom of such analysis, there is considerable reason for optimism. Drugs may exhibit selectivity of action beyond that predicted by target expression alone. Drugs that act at a single molecular target may have very different pharmacology and, as a result, different therapeutic uses. Three well-characterized model systems are highlighted to illustrate this point. The first model system is exemplified by nifedipine and verapamil, both of which act on L-type calcium channels. Both drugs are used to treat hypertension, but only verapamil can be used to produce atrioventricular block in patients with atrial fibrillation. The second model system describes the therapeutic exploitation of unusual conditions that occur in the ischemic myocardium to produce drugs that are more effective for suppressing ischemia-induced arrhythmias. The third model system discusses the mechanisms through which phosphodiesterase-5 (PDE5) inhibitors act selectively to facilitate penile erection while having little effect in the non-penile vasculature that also expresses PDE5.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

1,4-Dihydropyridines as calcium channel ligands and privileged structures.

1. The 1,4-dihydropyridine nucleus serves as the scaffold for important cardiovascular drugs-calcium antagonists-including nifedipine, nitrendipine, amlodipine, and nisoldipine, which exert their antihypertensive and antianginal actions through actions at voltage-gated calcium channels of the CaV1 (L-type) class. 2. These drugs act at a specific receptor site for which defined structure-activity relationships exist, including stereoselectivity. 3. Despite the widespread occurrence of the CaV1 class of channel, the calcium antagonists exhibit significant selectivity of action in the cardiovascular system. This selectivity arises from a number of factors including subtype of channel, state-dependent interactions. pharmacokinetics, and mode of calcium mobilization. 4. The 1,4-dihydropyridine nucleus is also a privileged structure or scaffold that can, when appropriately decorated substituents, interact at diverse receptors and ion channels, including potassium and sodium channels and receptors of the G-protein class.

Animals↗
PubMed2003

Drug targets in the voltage-gated calcium channel family: why some are and some are not.

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

Animals↗
PubMed2003

The 1,4-dihydropyridine nucleus: a pharmacophoric template part 1. Actions at ion channels.

The 1,4-dihydropyridine nifedipine is a prototypical example of the group of calcium channel blockers that also includes a number of second and third generation agents. These drugs enjoy substantial therapeutic prominence for their cardiovascular actions, including hypertension and angina. These actions are exerted at a specific member of the voltage-gated calcium channel family -the L-type channel. However, it is increasingly clear that the 1,4-dihydropyridine structure is a pharmacophoric template or "privileged structure" that, when appropriately substituted, can exert potent and selective actions at a diverse set of membrane receptors, including ion channels, G protein-coupled receptors and enzymes. This review will summarize the actions of 1,4-dihydropyridines at these receptors and advance the case that the 4-phenyl-1,4-dihydropyridine structure is a particularly versatile drug template. Part I of the review will summarize actions at ion channels and part II will summarize actions at other receptor systems.

Calcium Channel Blockers↗