Catecholamines receptor sites

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones for example, thyroid hormones increase both the number of 3 receptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a 3-adrenoceptor antagonist, in ameliorating symptoms of this disease. 

Cardiac pi-receptors and atrial and ventricular P2-receptors take part in positive inotropic response. Inhibition of catecholamines at P-adrenergic receptor sites interrupts the production of cAMP and inhibits calcium influx producing a negative inotropic effect that yields a reduction in the heart rate. 

Cocaine (alkaloid) is used medicinally solely as a surface anaesthetic (for abuse toxicity, see p. 192) usually as a 4% solution, because adverse effects are both common and dangerous when it is injected. Even as a surface anaesthetic sufficient absorption may take place to cause serious adverse effects and cases continue to be reported only specialists should use it and the dose must be checked and restricted. Cocaine prevents the uptake of catecholamines [adrenaline (epinephrine), noradrenaline (norepinephrine)] into S5nnpathetic nerve endings, thus increasing their concentration at receptor sites, so that cocaine has a built-in vasoconstrictor action, which is why it retains a (declining) place as a... 

Conformational isomerism is believed to be of great significance for drug-receptor and drug-enzyme interactions. For example, experimental data suggest that catecholamines such as norepinephrine and dopamine interact with their receptors in the antiperiplanar conformation. Furthermore, the preferred (pharmaco-phoric) conformation of acetylcholine at its muscarinic receptor sites is the synclinal conformer (Fig. 19). 

Before discussing the cyclics and MAOIs in more detail, we need to present the postulated biochemical hypotheses for depression. It is believed that depression results from a deficiency in biogenic amines, specifically catecholamines and serotonin, which act as central nervous system neurotransmitters (see Chapter 3). According to the catecholamine hypothesis, depression results from a deficiency in catecholamines (particularly norepinephrine) at varied neuron receptor sites in the brain. The cyclics are believed to block the reuptake of norepinephrine from the synaptic cleft. Thus, the result is a greater concentration of norepinephrine in the synaptic cleft, alleviating the hypothesized neurotransmitter deficiency. This cyclic-mediated process is thought to occur in the amygdala and reticular formation areas of the brain. 

Nicotiana tabacum contains 0.5-9% nicotine, which is the primary toxin. Nicotine binds to select acetylcholine receptors throughout the body known as nicotine receptors. This produces initial stimulation, but inhibition later, at the receptor sites throughout the nervous system. Low doses enhance the release of catecholamines and sympathetic stimulation. Higher doses produce parasympathetic stimulation. 

Wong SKF, Slaughter C, Ruoho AE, Ross EM. The catecholamine binding-site of the P-adrenergic-receptor is formed by juxtaposed membrane-spanning domains. J Biol Chem 1988 263 7925-7928. 

This leads to surface features resembling dopamine and may lead to selective binding at dopamine receptor sites (Figure 7). The polymer encapsulation matrix should protect the catecholamine from rapid metabolic inactivation. 

The other end of the psychiatric spectrum (Fig. 12-19) is depression. A catecholamine hypothesis that evolved here during the mid-1960s essentially stated that most of depression is associated with a relative or absolute catecholamine deficiency, especially NE at functionally important adrenergic receptor sites in the brain (Schildkraut, 1965). It is presumed that the opposite situation, which is excess catecholamines, may produce mania. Even though overly simplistic, the hypothesis served as a useful initiation into the developing complexity that followed. The NE deficiency, of course, can arise in any of several ways (1) decreased synthesis, (2) impairment of receptor binding, (3) storage impairment, (4) increased intracellular release, (5) increased oxidative metabolism rate, and (6) decreased receptor sensitivity. It is possible that different depression subtypes relate to dif-... 

Those agents that interact with calcium channels but have another primary site of action include agents acting on sodium channels (local anesthetics and phenytoin), catecholamine receptors (benextramine, nicergoline, phenoxy-benzamine, phenothiazines, pimozide, propranolol, and yohimbine derivatives), benzodiazepine receptors (diazepam and flurazepam), opiate receptors (loperamide and flu-peramide), and cyclic nucleotide phosphodiesterases (amrinone, cromoglycate, and papaverine), as well as barbiturates, cyproheptadine, indomethacin, and reserpine. 

Thiazide diuretics are used in the treatment of edema of cardiac and gastrointestinal origin and bring about a state of intravascular volume depletion. Because this depleted intravascular volume is replenished from the interstitial (edematous) sites, thiazide diuretics should not be administered too frequently. For example, hydrochlorothiazide is given every other day, and chlorthalidone is given once every 2 to 3 days. In small doses, thiazide diuretics are extremely effective in controlling essential hypertension. They exert their effects initially by bringing about volume depletion, then reduce the peripheral resistance and sensitivity of vascular receptor sites to catecholamine. Thiazide diuretics are also used in conjunction with antihypertensive medications. 

In small doses, thiazide diuretics are extremely effective in controlling essential hypertension. They exert their effects initially by bringing about volume depletion, then reduce the peripheral resistance and sensitivity of vascular receptor sites to catecholamine. Thiazide diuretics are also used in conjunction with antihypertensive medications. 

---