Adenosine monophosphate agonists

P2-Agonists cause airway smooth muscle relaxation by stimulating adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). Other non-bronchodilator effects have been observed, such as improvement in mucociliary transport, but their significance is uncertain.11 P2-Agonists are available in inhalation, oral, and parenteral dosage forms the inhalation route is preferred because of fewer adverse effects. 

The short-acting / -agonists (Table 80-1) are the most effective broncho-dilators available. /J2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

Figure 1.10 Model of a G protein-coupled receptor with 7 membrane-spanning domains. Binding of an agonist to the receptor causes GDP to exchange with GTP. The a-GTP complex then dissociates from the receptor and the py complex and interacts with intercellular en mes or ion channels. The Py complex can activate an ion channel or possibly also interact with intercellular enzymes. GDP, guanine diphosphate GTP, guanine triphosphate cAMP, cyclic adenosine monophosphate PKC, protein kinase C PLC, phospholipase C DAG, diacylglycerol.

M19. Mitra, S. P., and Carraway, R. E., Synergistic effects of neurotensin and beta-adrenergic agonist on 3,5-cyclic adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3 cells. Biochem. Pharmacol. 57, 1391-1397 (1999). 

Q6 Salbutamol is a selective beta-2-adrenoceptor (/ -adrenoceptor) agonist which is effective in relieving mild to moderate bronchoconstriction. Inhalation of salbutamol induces bronchodilation by acting on /J2-receptors on bronchial smooth muscle this lasts for approximately three to five hours. It also inhibits mediator release and improves the clearance of mucus from the lung. Stimulation of the /02-receptor increases the cellular concentration of cyclic adenosine monophosphate cAMP and activates a protein kinase. This kinase in turn inactivates myosin-light-chain kinase, an enzyme necessary for contraction in smooth muscle, and so relaxes bronchial smooth muscle. 

Adrenoceptors are proteins embedded in the cell membrane that are coupled through a G-protein to effector mechanisms that translate conformational changes caused by activation of the receptor into a biochemical event within the cell. All of the )3-adrenoceptors are coupled through specific G-proteins (Gg) to the activation of adenylyl cyclase (45). When the receptor is stimulated by an agonist, adenylyl cyclase is activated to catalyze conversion of ATP to cyclic-adenosine monophosphate (cAMP), which diffuses through the cell for at least short distances to modulate biochemical events remote from the synaptic cleft. Modu-lationof biochemical events by cAMP includes a phosphorylation cascade of other proteins. cAMP is rapidly deactivated by hydrolysis of the phosphodiester bond by the enzyme phosphodiesterase. The a,-receptor may use more than one effector system, depending on the location of the receptor however, to date the best understood effector system of the a,-receptor appears to be similar to that of the )3-re-... 

Figure 23-2 depicts adrenoceptor-G protein interaction, fi-and dopamine (DA)i-adrenoceptor agonists activate the stimulatory G protein, Gs, which dissociates from the receptor and activates membrane-bound adenyl cyclase (AC). 2- and DA2-agonists activate the inhibitory G protein, Gi, which dissociates from the receptor and blocks AC. AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which stimulates protein kinases, resulting in alterations in cellular functions. 

FIGURE 23-2. Adrenoceptor-G protein interaction. AC = adenylate cyclase a-agonist = a-adrenergic receptor agonist ATP = adenosine triphosphate agonist = jS-adrenergic receptor agonist cAMP = cyclic adenosine monophosphate Gs = G stimulatory protein Gi = G inhibitory protein. (Adapted with permission from ref. 106.)... 

These drugs inhibit the actions of cellular phosphodiesterase, resulting in increased levels of cyclic adenosine monophosphate (cAMP). The actions are tissue-specific and mimic tor potentiate) the effects of sympathetic beta agonists. Other bronchodilatory actions may also be present, but as yet are undefined. 

Fig. 2. Proposed mechanism of inbition of smooth muscle contraction by p2-agonists, where AMP is adenosine monophosphate, cAMP i adenosine monophosphate, ATP is adenosine triphosphate, and -P is an attached phosphate.

Nonglycosidic positive inotropic drugs can be divided into two main classes those that act via stimulating the synthesis of cyclic adenosine monophosphate (cAMP), such as adrenergic and dopaminergic agonists and those that inhibit the hydrolysis of cAMP, such as phosphodiesterase 3 (PDE3) inhibitors. 

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