0-Adrenergic potency

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. 

Division of the receptors in the adrenergic nervous system into two classes (a and P) was proposed in 1948 (39) when a difference in the rank order of potency of epinephrine (1, R = CH ), norephinephrine (1, R = H), and isoproterenol [7683-59-2], C H yNO, (1, R = CH(CH3)2) was noted to depend on the organ examined. Eurther subdivision into groups P2 proposed in 1967 (40). Both types of P-adrenoceptors are found throughout the... 

Some alicyclic 1,2-diamine derivatives have recently been shown to have interesting CNS properties. For example, eclanamine (34) is an antidepressant with a rapid onset of action. The reasons for its potency are not as yet clear but pharmacologists note that the drug desensitizes adrenergic alpha-2 receptors and antagonizes the actions of clonidine. The synthesis of eclanamine starts with attack of cyclopentene oxide (30) by dimethylamine (to give 31). This product is converted to the mesylate by reaction with sodium hydride followed by mesyl chloride. Attack of... 

The best statistical parameters were obtained by correlating the in vivo selectivity with the Vdif descriptor defined with respect to the oqa-AR supermolecule. It is worth noting that the oqa is the adrenergic receptor subtype of functional relevance for the urethra tissue (dog model) [8]. Thus, ligands showing high potency and selectivity for the lower urinary tract are those, which better fit the volume of the supermolecule that represents the binding site of the ala-AR subtype. 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

The net result is that low potency antipsychotics cause more histamine-blocking, acetylcholine-blocking, and a-1 adrenergic blocking side effects. The high potency antipsychotics are more likely to produce dopamine-blocking side effects. Now, let s take a brief look at each of the specific medications. 

Pharmacology Carvedilol, an antihypertensive agent, is a racemic mixture in which nonselective -adrenoreceptor blocking activity is present in the S(-) enantiomer and -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. 

Sympathomimetic Adrenergic receptor activity 2 potency Route Onset (min) Duration (h)... 

Sedation is common after use of all antipsychotic drugs and is especially notable with the low-potency phenoth-iazines this is a result of their activity at aj-adrenergic and Hi-histaminergic receptors. However, sedation decreases during long-term treatment, and many patients become tolerant to this effect. Single daily doses given at bedtime minimize this problem. 

Antipsychotic agents may have several cardiovascular effects. Medication-induced hypotension is generally more problematic with lower-potency neuroleptics than with other antipsychotics and appears to be mediated through tti-adrenergic blockade. Besides increases in heart rate that may be the result of hypotension, antipsychotics with appreciable anticholinergic effects (see Clinical Implications, below) can lead to tachycardia (Gutgesell et ah, 1999). 

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