The mechanism-of-action of clozapine, the prototypical atypical anti-psychotic drug, has been the subject of intense research aimed at revealing the key property of this drug that allows it to have superior antipsychotic activity relative to the more classical antipsychotic drugs. Evidence indicates that clozapine's high affinity interactions with the 5HT-2A receptor may be a key factor. In addition, clozapine has high affinity for the 5HT-2C, 5HT-6, and 5HT-7 receptors. Until recently it has been assumed that clozapine is a classical competitive antagonist at the 5HT-2A receptor. However, preliminary data in this proposal reveal that clozapine is an inverse agonist at the constitutively activated form of the 5HT-2A receptor, created by site-specific mutagenesis. In order to explore the possibility that clozapine's atypical activity may be related to its inverse agonist activity at the 5HT-2A receptor, the effects of a group of typical and atypical antipsychotic drugs on the constitutively activated 5HT-2A receptor will be determined. It is anticipated that if 5HT-2A inverse agonist activity is a critical factor in atypical drug properties, a correlation will be found between inverse agonist activity and atypical antipsychotic activity. In order to ascertain the specificity of the inverse agonist activity of clozapine at the 5HT-2A receptor, the effects of clozapine and other atypical antipsychotic drugs at constitutively activated forms of the 5HT-2C, 5HT-6 and 5HT-7 receptors will be determined. It is anticipated that these studies should confirm or refute the hypothesis that 5HT-2A receptor inverse agonist activity is critical to atypical antipsychotic activity, and may reveal a possible involvement of the 5HT-2C, 5HT-6 or 5HT-7 in atypical drug actions. It is also anticipated that similarities and differences in the pharmacology of the activated state of the four 5HT receptors studied will be revealed: this information may be important in future drug development aimed at developing inverse agonists for therapeutic purposes.
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