Calcium agonists

Pyrrol Derivative Structures and Effective Concentrations for 36 Calcium Agonists 

FIGURE 6.35 Correlation between calculated and predicted effective concentrations (ECjq) for 36 Ca agonists with the leave-one-out technique. The standard deviation is 0.59. 

The correlation of structures and biological activities with the aid of 2D RDF descriptors leads to reliable predictions. Nevertheless, the matter of structure-activity relationship is a complex problem depending on many atomic and molecular properties and experimental conditions. It is advisable to use several descriptors in combination with 2D RDF descriptors and to adjust the latter ones by adequate selection of calculation conditions for the specific task. 

Even though it has been known for 100 years or more that stereoselectivity plays an important role in drug activity, chiral drugs have been developed and used as race-mates while neglecting the fact that they comprise mixtures of two or more compounds that may have quite different pharmacological properties [98,99]. An example with dramatic consequences is Thalidomide (2-(2,6-dioxo-3-piperidyl)isoindol-l,3-dion, Contergan). 

---

Gould, R.J., Murphy, K.M.M. and Snyder, S.H. (1982) [3H]Nitrendipine-labeled calcium channels discriminate inorganic calcium agonists and antagonists. Proceedings of the National Academy of Sciences of the United States of America, 79, 3656-3660. 

Hoffmeister, F. and Tettenbom, D. Calcium agonists and antagonists of the dihydropyridine type Antinociceptive effects, interference with opiate-p-receptor agonists and neuropharmacological actions in rodents, Psychopharmacology 1986, 90, 299-307. 

Meyer H, et al. Bayer-Symposium, 9th Cardiovascular Eff. Dihydropyridine-Type Calcium Antagonists Agonists, Rigid Calcium Agonists of the Nifedipine Type Geometric Requirements for the Dihydropyridine Receptor 1985 90-103. 

A further practical consideration of using low ion concentration to induce tone is that the contractions can be small and not well maintained. A possible solution to this problem is to enhance the tone by using the calcium agonist. Bay K 8644 (45), but this further complicates the assay [57], A simpler alternative is to use a spasmogen-induced contraction that can be potently relaxed by cromakalim (1) (for example, noradrenaline-induced contraction in vascular tissue), and then compare the compound under examination against high K ion concentration [58]. 

Interestingly, 1,4-dihydropyridines, such as Bay K 8644 (2.13), CGP 28392 (2.14) and YC-170 (2.15), have been discovered which show calcium agonist effects. For instance, these compounds demonstrate positive cardiac inotropic and vasoconstrictor activities [81]. Bay K8644 increases twitch tension in guinea-pig atria in a frequency-dependent manner and prolongs action poten-... 

Goldman, S. and Stoltefuss, J. (1991) 1,4-Dihydropyridines effects of chirality and conformation on the calcium antagonist and calcium agonist activities. Angewandte Chemie 30 1555-1578. 

Nowycky MC, Fox AP, Tsien RW. Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 1985 316(6027) 440-3. 

Another mechanism in initiating the contraction is agonist-induced contraction. It results from the hydrolysis of membrane phosphatidylinositol and the formation of inositol triphosphate (IP3)- IP3 in turn triggers the release of intracellular calcium from the sarcoplasmic reticulum and the influx of more extracellular calcium. The third mechanism in triggering the smooth muscle contraction is the increase of calcium influx through the receptor-operated channels. The increased cytosolic calcium enhances the binding to the protein, calmodulin [73298-54-1]. 

Another major second messenger in cells is calcium ion. Virtually any mammalian cell line can be used to measure transient calcium currents in fluorescence assays when cells are preloaded with an indicator dye that allows monitoring of changes in cytosolic calcium concentration. These responses can be observed in real time, but a characteristic of these responses is that they are transient. This may lead to problems with hemi-equilibria in antagonist studies whereby the maximal responses to agonists may be depressed in the presence of antagonists. These effects are discussed more fully in Chapter 6. 

FIGURE 5.6 Calcitonin receptor responses, (a) Real-time melanin dispersion (reduced light transmittance) caused by agonist activation (with human calcitonin) of transfected human calcitonin receptors type II in melanophores. Responses to 0.1 nM (filled circles) and lOnM (open circles) human calcitonin, (c) Dose-response curves to calcitonin in melanophores (open circles) and HEK 293 cells, indicating calcium transient responses (filled circles). 

---