Adrenergic selectivities

Studies on the Mechanism of Fluorine-Induced Adrenergic Selectivities... 

Conformational Effects of Fluorine Substitution. Mechanisms considered to explain adrenergic selectivities of fluorinated norepinephrine (and related adrenergic agonists) have included 1) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain or 2) a direct effect of the C-F bond on agonist-receptor interaction. In the first formulation, proposals were made that fluorine situated in a position ortho (position 2 or 6) to the ethanolamine side chain creates a bias for side chain conformations favorable for binding to p- and a-adrener-gic receptors, respectively. 

Fluorine-Induced Electronic Effects and Adrenergic Selectivities. It... 

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Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

Because of the widespread nature of adrenoceptors, nonselective P-agonists can produce many undesirable side effects. Therefore, before adrenergic agonists could become widely used in the treatment of asthma, some selectivity in action was needed. Whereas epinephrine and ephedrine have significant agonist activity at both a and P adrenoceptors, isoproterenol is a selective agonist at the P receptor (39). However, isoproterenol does not distinguish between the P and receptors and it is not active orally. 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Prazosin, a selective a -adrenoceptor antagonist, exerts its antihypertensive effect by blocking the vasoconstrictor action of adrenergic neurotransmitter, norepinephrine, at a -adrenoceptors in the vasculature (200,227,228). Prazosin lowers blood pressure without producing a marked reflex tachycardia. It causes arteriolar and venular vasodilation, but a significant side effect is fluid retention. Prazosin increases HDL cholesterol, decreases LDL cholesterol, and does not cause glucose intolerance. 

In general, activation of alpha-1 adrenergic receptors causes a contraction of smooth muscle and of blood vessels, pilomotor muscles, dilator pupillae, vas deferens, nictitating membrane, splenic capsule, and sphincters of the intestine and urinary bladder and of the bile duct. An exception is the relaxation of the smooth muscle of the intestine. Prazosin [19216-56-9] indoramin [26844-12-2] and WB-4101 are relatively selective antagonists of these receptors. 

Catecholamines are also intimately involved in cardiac function, with 3-sympathetic agonists having a generally stimulant action on the heart. Some effort has thus been devoted to the synthesis of agents that would act selectively on the heart. (Very roughly speaking, 3 -adrenergic... 

Non-selective (3-adrenergic receptor agonists, particularly adrenaline (qunephrine), are used in cardiovascular... 

Relatively selective stimulation of Pi-adrenergic receptors can be achieved with dobutamine. This is a racemic drug of which both isomers activate the Pi-receptor, and in addition the (-) isomer activates ( -receptors whereas the (+) isomer activates p2-receptors the simultaneous activation of ai- and p2-receptors results in no major net effect on peripheral resistance, and thus the overall cardiovascular effects are mediated by Pi-stimulation leading to increases in cardiac contractility and output. Dobutamine is used for the short-term treatment of acute cardiac failure and for diagnostic purposes in stress echocardiography. 

Clinically used p-adrenergic receptor antagonists ( P-blockers ) are either px-selective (e.g. bisoprolol, metoprolol, atenolol, betaxolol) or non-selective,... 

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