mCPP has been employed to probe brain 5-HT function in human beings. The drug alters a number of neuroendocrine parameters and elicits profound behavioral effects, with anxiety as a prominent symptom. mCPP elevates corticotropin and prolactin secretion (probably via a combination of 5-HTj and 5-HT2A/2C receptor activation) and increases growth hormone secretion (apparently by a 5-HT-independent mechanism). 5-HT2A/2C receptors appear to mediate at least part of the anxiogenic effects of mCPP, since 5-HT2A/2C receptor antagonists attenuate mCPP-induced anxiety.
Clinical effects of 5-HT-related drugs often exhibit a significant delay in onset, notable in drugs used to treat affective disorders such as anxiety and depression (see Chapter 17). This delayed onset may relate to adaptive changes in 5-HT receptor density and sensitivity after chronic drug treatments. Laboratory studies have documented agonist-promoted receptor subsensitivity and down-regulation of 5-HT receptor subtypes. However, an unusual adaptive process, antagonist-induced down-regulation of 5-HT2C receptors, occurs in laboratory animals after chronic treatment with receptor antagonists. Many clinically effective drugs, including clozapine, ketanserin, and amitriptyline, exhibit this unusual property. These drugs, as well as several other 5-HT2A/2C receptor antagonists, possess negative intrinsic activity or inverse agonism, reducing constitutive (spontaneous) receptor activity as well as blocking agonist occupancy (competitive antagonism). Other 5-HT2A/2C receptor antagonists act in the classical manner, simply blocking receptor occupancy by agonists. Even though there is modest evidence for constitutive activity in vivo, drug development has been further refined by focusing on reduction of preexisting constitutive neuronal activity as opposed to blockade of excess neurotransmitter action.
Ketanserin (sufrexal) potently blocks 5-HT2A receptors, less potently blocks 5-HT2C receptors, and has no significant effect on 5-HT3 or 5-HT4 receptors or any members of the 5-HT1 receptor family. Ketanserin also has high affinity for a adrenergic and histamine H1 receptors.
Ketanserin lowers blood pressure in patients with hypertension, causing a reduction comparable to that seen with b adrenergic-receptor antagonists or diuretics. The drug appears to reduce the tone of both capacitance and resistance vessels. This effect likely relates to its blockade of aj adrenergic receptors, not its blockade of 5-HT2A receptors. Ketanserin inhibits 5-HT-induced platelet aggregation but does not greatly reduce the capacity of other agents to cause aggregation. Severe side effects after treatment with ketanserin have not been reported. Its oral bioavailability is ~50%; its plasma t122 is 12—25 hours. The primary mechanism of inactivation is hepatic metabolism. Ketanserin is available in Europe but not in the U.S.
Chemical relatives of ketanserin such as ritanserin are more selective 5-HT2A receptor antagonists with low affinity for a1 adrenergic receptors. However, ritanserin, as well as most other 5-HT2A receptor antagonists, also potently antagonize 5-HT2C receptors. The physiological significance of 5-HT2C-receptor blockade is unknown. MDL 100,907 is the prototype of a new series of potent 5-HT2A receptor antagonists, with high selectivity for 5-HT2A versus 5-HT2C receptors.
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