Adrenergic activators

Adrenergic receptors are located throughout the body on neuronal and non-neuronal cells where they mediate a diverse range of responses to the endogenous catecholamines adrenaline and noradrenaline. To date, nine adrenergic receptors have been cloned. The classification of epinephrine receptors into a-receptors and P-receptors stems from Ahlquist (1948). Epinephrine and five related substances in a number of bioassays acted in either an excitatory or an inhibitory manner. The results could only be explained by postulating two different receptors, i.e. the a- and the P-receptors. 

Three genes encoding Oj-adrenergic receptor subtypes have been identified from several species, termed 02a, Ojb, and ttjc, respectively (for review see Hein 2001). The ajB-receptor shows primarily peripheral expression in kidney, liver, lung, and heart. 

Antagonists prazosin phentolamine yohimbine Oj-adrenergic receptors 

Antagonists yohimbine phentolamine prazosin Pi-adrenergic receptors 

Agonists isoproterenol epinephrine norepinephrine Antagonists oetaxolol ICI 118,551 Pi-adrenergic receptors 

---

The properties of -adrenoceptor blockers that contribute to antiarrhythmic effects are antagonism of neural/humoral P-adrenergic activity, and antagonism of catecholamine-mediated electrophysiological properties, ie, increase refractory period and decrease in the rate of diastoHc depolarization, ie, decrease automaticity and slow atrioventricular conduction (1,2). 

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77)... 

It has by now been reasonably well established that an ethanolamine function appropriately linked to an aromatic ring is a prerequisite for beta adrenergic activity and/or antagonism. Examples have been met above where those two moieties are attached directly as well as examples where the funetions are separated by an oxymethylene fragment. It has reeently been found that beta blocking activity is retained even when a earbonyl is inserted between the extra oxymethylene... 

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

Norepinephrine is a potent a-adrenergic agent with less pronounced P-adrenergic activity. Doses of 0.01 to 3 mcg/kg per minute can reliably increase blood pressure with small changes in heart rate or cardiac index. Norepinephrine is a more potent agent than dopamine in refractory septic shock.24,27-28... 

Dopamine is a a- and P-adrenergic agent with dopaminergic activity Low doses of dopamine (1 to 5 mcg/kg per minute) maintain renal perfusion, higher doses (greater than 5 mcg/kg per minute) exhibit a- and P-adrenergic activity and are frequently utilized to support blood pressure and to improve cardiac function. Low doses of dopamine should not be used for renal protection as part of the treatment of severe sepsis.24,27-28... 

The answer is d. (Katzung, p 130J Epinephrine has a positive ionotropic and chronotropic effect on the heart because of its pradrenergic activity It also has a-adrenergic activity that causes vasoconstriction in the vascular beds. These actions result in a rise in systolic blood pressure. Epinephrine also has p2-adrenergic activity, which causes vasodilation in skeletal muscle. Because of this latter effect, total peripheral resistance can fall, resulting in a drop in diastolic pressure, particularly at low doses of epinephrine. 

There might be an increased ratio of cholinergic to adrenergic activity in depression, and the reverse in mania 892... 

Virkki, L. and M. Nikinmaa. 1993. Tributyltin inhibition of adrenergically activated sodium/proton exchange in erythrocytes os rainbow trout (Oncorhynchus mykiss). Aquat. Toxicol. 25 139-146. 

Deficiency of acetylcholine causes an imbalance in cholinergic-adrenergic activity and can increase the risk of manic episodes. 

Among methoxy-substituted yohimbine alkaloids, only 11-methoxy-a-yohim-bine (95) and 1 l-methoxy-3-epi-a-yohimbine (106) were tested for a-adrenergic activity, and they showed only weak a2-adrenoceptor blocking effect (347). On the other hand, venenatine (107) has reserpinelike activity and shows synergism with reserpine (109). Furthermore, alstovenine (96) displays monoamine oxidase inhibitor activity (348). 

Table 3 Differences in enthalpy (H, cal/mole) entropy ( SQ, cal/mole.deg) and ratios of adrenergic activities Rc ) of the enantiomers of adrenergic drugs.

Masson, S., Masseroh, M., Fiordaliso, F., et al. (1999) Effects of a DA(2)/alpha(2) agonist and a beta(l)-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion. J. Cardiovasc. Pharmacol. 34, 321-326. 

It should be mentioned that the substituted ethanolamine group in the structure of )3-adrenobIockers is similar to that of many compounds with agonistic adrenergic activity (isoproterenol (II.1.9), albuterol (11.1.21), and others), and therefore it is possible that it may be responsible for high affinity of the examined adrenoblockers with )3-adrenergic receptors. 

They are used for arrhythmias associated with nervous stress, myocardial infarction, and thyrotoxicosis accompanied by elevated adrenergic activity. Moreover, many antiarrhythmic drugs themselves can cause arrhythmia, especially in patients with ischemic heart disease. The examined 8-adrenergic receptor blockers are an exception. Having said that, practically all )3-adrenergic receptor blockers can be used as antiarrhythmics. 

Pharmacology Sympathomimetic agents produce -adrenergic stimulation (vasoconstriction), - -adrenergic stimulation (increase myocardial contractility, heart rate, automaticity, and AV conduction), and 2-adrenergic activity (peripheral vasodilation). Dopamine also causes vasodilation of the renal and mesenteric, cerebral, and coronary beds by dopaminergic receptor activation. 

Levonordefrin (Neo-Cobefrin) is an active optical isomer of nordefrin that has ai-adrenergic activity and... 

The alpha-2-adrenoreceptor antagonist yohimbine increases adrenergic activity and may provoke anxiety and panic symptoms in patients but no or only mild symptoms in healthy volunteers. Yohimbine infusions evoke intrusive symptoms, i.e. flashbacks together with significant increase of... 

---