Ever
since the cloning and characterization of the distribution of the D3 and D4
receptors, which revealed a limbic and cortical distribution, there has been considerable
speculation about the role of these receptors in schizophrenia and the
mechanism of action of antipsychotic drugs. (Ichikawa et al., 2000)
As
specific antagonists have become available, it has been possible to test their
efficacy in animal models of psychosis, cognition, and motor function, as well
as to carry out some clinical trials in schizophrenia. Recently, Reavill et al.
reported that SB-277011-A, which has high affinity and selectivity for the D3
receptor and good brain bioavailability, has an atypical antipsychotic drug
profile. This compound was active in preventing isolation-induced deficits in
prepulse
inhibition but was not effective in blocking either amphetamine- or
phencyclidine (PCP)-induced locomotor activity or, by using microdialysis, to
increase prefrontal cortical DA release in rats. However, subchronic
administration of SB-277011-A selectively decreased the firing rate of A10, but
not A9, DA neurons in the rat, indicating a clozapine-like profile. These are
the most promising data yet that a selective antagonist of D3 receptors might be
useful in the treatment of psychosis.
On
the basis of the finding that the affinity of clozapine for the cloned DA D4
receptor was two to three times greater than that for the D2 receptor, Van Tol
et al. Suggested that blockade of the D4 receptor was the basis for the
superiority of clozapine over the typical neuroleptic drugs in the treatment of
schizophrenia. Other investigators have found less of a difference between the
affinity of clozapine for D2 and D4 receptors. Several typical antipsychotic drugs,
including haloperidol, have nearly equivalent affinity for D2 and D4 receptors,
suggesting that D4 affinity per se does not convey any special advantages for
an antipsychotic drug. The preclinical behavioral and electrophysiologic profile
of highly selective D4 antagonists provides mixed evidence with regard to
antipsychotic action associated with this receptor. A D4/antagonist, NRA0025, appears to have promise as an
antipsychotic agent based on its preclinical profile. A clinical trial of a
selective D4 antagonist showed no sign of activity. (Ichikawa
et al., 2000)
A
compound with potent 5-HT2A and D4 antagonist properties, finanserin, was also
ineffective. Further clinical trials of compounds that have D4 or D3
antagonism, or both, together with high affinities for 5-HT1A or receptors, and without D2 affinity seems indicated. (Ichikawa
et al., 2000)