Postsynaptic a-adrenoceptor antagonists

POSTSYNAPTIC a-ADRENOCEPTOR ANTAGONISTS [SEDA-31, 363 SEDA-32, 391 SEDA-33, 425]... 

The use of postsynaptic a-adrenoceptor antagonists in older patients with benign prostatic hyperplasia has been reviewed [102 ]. 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Postsynaptic a-adrenoceptors have been characterized in afferent and efferent arterioles isolated from rabbit renal cortex [263]. In both the afferent and efferent arteriole selective a 1-adrenoceptor agonists produced concentration-dependent vasoconstrictor responses with the maximum responses being equal to that of norepinephrine. Selective a 2-receptor agonists had less of an effect. The a 1-receptor antagonist, prazosin, produced a rightward shift in the concentration-response curve to norepinephrine, while the selective a 2-receptor antagonist, rauwolscine had no... 

Alpha-adrenoceptor antagonists inhibit the activation of a adrenoceptors by catecholamines. In the cardiovascular system these receptors are mainly located on the surface of smooth muscle cells in the walls of arteries and veins. On activation, they mediate an increase in intracellular free calcium, which induces smooth muscle contraction. Inhibition by an a antagonist causes arterial or venous vasodilatation. The postsynaptic effect is mainly mediated by ol adrenoceptors whereas o2 adrenoceptors are found on the presynaptic membranes of the sympathetic neurones. Activation of o2-adreno-ceptors results in auto-inhibition of catecholamine release. 

Trazodone (SEDA-7,19-21) is a triazolopyridine derivative that selectively but weakly inhibits 5-hydroxytrypta-mine (5-HT) re-uptake and is an alpha-adrenoceptor antagonist at both presynaptic and postsynaptic receptors (1). During long-term administration it down-regulates serotonin receptors (2). 

Indoramin is a postsynaptic selective alphai-adrenoceptor antagonist that is chemically distinct from the quinazo-lines. Unlike some other alpha-blockers, indoramin lowers blood pressure without a resulting reflex tachycardia or postural hypotension (1). However, it has largely been supplanted by more modern drugs, such as doxazosin, prazosin, and terazosin. 

Considerable attention has been paid to the ultimate postsynaptic effects of increased neurotransmitters in the synapses. In tests of postsynaptic effects, cAMP concentrations have consistently decreased rather than increased, in spite of the presumably longer duration of action of the transmitters. In addition, the number of postsynaptic -adrenoceptors has shown a measurable decrease that follows the same delayed time course as clinical improvement in patients. Thus, the initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of receptors. Decreases in norepinephrine-stimulated cAMP and in B-adrenoceptor binding have been conclusively shown for selective norepinephrine uptake inhibitors, those with mixed action on norepinephrine and serotonin, monoamine oxidase inhibitors, and even electroconvulsive therapy. Such changes do not consistently occur after the selective serotonin uptake inhibitors, 2 receptor antagonists, and mixed serotonin antagonists. 

A more potent and selective 5-HTlx ligand is WAY 100635 (Table 8). The compound displays a high affinity for the 5-HTiA receptor (pKj=9.1), a weak affinity for Oj-adrenoceptors (pKj=6.4) and no affinity for the other receptors tested [48] (Table 8). In functional tests WAY 100635 acts as an antagonist at both presynaptic somatodendritic and postsynaptic 5-HT1A receptors [49]. 

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