emotional response. Paranoid psychosis, on the other hand, is a psychotic disorder in
which delusions, generally persecutory but sometimes grandiose, are the dominant
abnormality (e.g., “the government has planted listening devices in my teeth and are
monitoring everything that I do; they are against me, everyone is against me”). Finally,
affective psychoses are a group of psychoses characterized by a single disorder of
mood, typically extreme depression, which dominates the mental life of the patient,
incapacitating the patient and sometimes culminating in suicide. Clearly, the psychoses
are an exceedingly complex and heterogeneous array of mental state abnormalities. It
is daunting to think that a single receptor (or family of receptors) can subserve such a
complicated assortment of psychiatric illnesses.
Nevertheless, dopamine antagonists are successful antipsychotic drugs (neuroleptics)
and are very widely used in the symptomatic management (not cure) of all forms of
psychosis. The antidopaminergics were discovered in 1952 by Delay and Daniker who,
when working for the French pharmaceutical company Rhône-Poulenc, became the
first to synthesize chlorpromazine (1.3) while searching for a drug with improved anti-
histaminic properties. Instead, they recognized the major sedative action of the drug in
agitated schizophrenics, and a new era in the management of affective disorders began.
The tricyclic thymoleptics were derived from chlorpromazine a few years later.
The first and original ring system used in neuroleptic drugs is phenothiazine (4.88).
In order for neuroleptic activity to occur, the distance between the ring nitrogen and
side-chain nitrogen must be three carbon atoms. Shorter chains (like promethazine with
an ethylamine side chain) are merely antihistamines with a strong sedative action. For
optimal activity, the ring substituent in position 2 must be electron attracting.
Thioxantheneslack the ring nitrogen of phenothiazine, and the side chain is attached
by a double bond. In all cases, the cisisomer (relative to the substituted phenyl ring)
is more active. Electron-attracting substituents seem to have a cumulative effect. For
instance, pifluthixol (4.89), with a fluorine and a trifluoromethyl substituent, is 5–10
times more potent than its parent flupenthixol (4.90), and has an inhibitory effect
(IC 50 =9.7× 10 −^10 M) on the DA-sensitive adenylate cyclase of the striatum.
Thebutyrophenones are chemically unrelated to the phenothiazines, but show a simi-
lar antipsychotic action. They were developed by P. A. Jansen and derived from fentanyl-
type analgesics (see chapter 5). More than 4000 derivatives have been synthesized, of
which the three most widely used antipsychotics are shown. Pimozide (4.91) is clearly
derived from benperidol (4.92), even though it is no longer a butyrophenone.
Recently a number of novel, non-classical chemical structures, referred to as “atypi-
cal neuroleptics,” have been described: clozapine (4.93), risperidone (4.94), olanzapine
(4.95), and sertindole (4.96). These atypical neuroleptics have two distinguishing
244 MEDICINAL CHEMISTRY