identified. The 5 - HT 5 familyis a group of receptors that is coupled to neither adenylyl
cyclase nor PI-PLC; the family has two subtypes: 5-HT5Aand 5-HT5B.
This array of receptor families and subtypes may be grossly divided into two groups
on the basis of their protein structure. The 5-HT 3 receptor has a tube-like structure and
is a transmembrane ion channel protein. The other 5-HT receptor families tend to
exhibit the typical seven transmembrane-spanning segments common to receptors cou-
pled with G-proteins. The 5-HT receptors can also be distributed into two groups on the
basis of their gene structures. The 5-HT 2 receptors are derived from genes that contain
multiple introns. Other 5-HT receptors, such as the 5-HT 1 family, are encoded by genes
lacking introns.
The various receptors also subserve different potential clinical applications. 5-HT1A
receptors are involved in psychosis, depression, and anxiety. 5-HT1Dand 5-HT1Frecep-
tors seem to be involved with migraine headache. 5-HT2Areceptors are useful thera-
peutic targets for schizophrenia and depression. 5-HT2Breceptors, on the other hand,
influence gastric motility and migraine headaches. The potential uses for 5-HT2Cligands
include anxiety, depression, obesity and cognitive disorders; 5-HT2Cknockout mice
have cognitive disorders, epilepsy and obesity. Because of the widespread presence of
neurons in the gastrointestinal tract, 5-HT 3 receptors have potential for the treatment of
irritable bowel syndrome and chemotherapy-induced vomiting. Other potential thera-
peutic indications for 5-HT 3 drugs include anxiety, anorexia, and drug abuse. 5-HT 4
receptors are located centrally in the brain and peripherally in a variety of organs;
accordingly, centrally active 5-HT 4 ligands may play a role in the treatment of schizo-
phrenia or Parkinson’s disease, while peripherally active ligands may be useful for
urinary incontinence or irritable bowel syndrome. 5-HT 6 receptor ligands are effective
antipsychotics and antidepressants. 5-HT 7 receptor active agents may have use in the
treatment of pain associated with migraine.
4.5.3 Serotonin Receptors: Presynaptic Drug Effects4.5.3.1 Serotonin Synthesis Inhibitors
Synthesis inhibitors block tryptophan hydroxylase, the first rate-determining enzyme in
serotonin synthesis. Although p-chlorophenylalanine (4.111) can decrease serotonin
levels by more than 90%, this agent does not cause the sedation that is seen after cate-
cholamine depletion with reserpine. Therefore, reserpine, although capable of deplet-
ing 5-HT vesicles, causes sedation by a catecholaminergic mechanism that inhibits
uptake-2. It acts on the membrane of the synaptic vesicle and seems to prevent 5-HT
and catecholamine uptake into the granule.
252 MEDICINAL CHEMISTRY