Potent agonists

The effects of N-substituents on dopamine congeners are numerous and well documented. Generally, compounds active at DA2 receptors retain or have enhanced activity as tertiary amines. By contrast, compounds active at DA receptors generally are most active as primary, or sometimes secondary amines with one major exception substitution of the nitrogen with di-n-propyl groups leads to compounds active at DA receptors. This effect is so powerful that even in dopamine congeners which possess the so-called alpha rotameric moiety, not normally seen in DAi agonists, potent action is observed (28). 

In many cell types, D2 receptor stimulation has an effect on enzymes metabolizing membrane lipids. We have mentioned above that in mesenchyme-derived cells and in striatal neurons, D2 agonists stimulate the activity of PLCp by mobilizing Gpy complex, and produce an inositol triphosphate-dependent Ca2+ release from intracellular stores (Ghahremani et al., 1999). In CHO cells stably transfected with D2 receptors, D2 agonists potently enhance the release of arachidonic acid when intracellular Ca2+ levels are already enhanced. This effect was observed following stimulation of various Gi/o-coupled... 

N orferruginin e] (tropane) Synthetic nACh-R agonist (potent)... 

Ghosh B, Antonio T, Zhen J, Kharkar P, Reith M. E. A, Dutta A. K.. Development of (S)-N6-(2-(4-(Isoquinolin-l-yl)piperazin-l-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydroben-zo[d]-thiazole-2,6-diamine and Its Analogue as a D3 Receptor Preferring Agonist Potent in Vivo Activity in Parkinson s Disease /Animal Models, J. Med. Chem. 2010. p. 1023 -1037. DOI 10.1021/jm901184n... 

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

DOI (294) and a-methyl-5-HT (295) are selective 5-HT2 receptor agonists. Ketansetin (296) and ritansetin (297) are potent and selective 5-HT2 antagonists. SB 200646 (298) is an antagonist which has greater selectivity toward 5-HT2g and receptors compared to the 5-HT2 subtype. 

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

Fig. 10. The postulated interaction of a-adrenoceptor agonists with the receptor. The Easson-Stedman hypothesis suggests that (R)-noradrenaline is most potent owing to its three points of attachment () to the adrenoceptor, whereas dopamine and (5)-noradrenaline are equal in activity, but less active...

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