S18327, a Novel, Potential Antipsychotic Displaying
Marked Antagonist Properties at a1- and a2Adrenergic Receptors: I. Receptorial, Neurochemical,
and Electrophysiological Profile
Introduction:
Although neuroleptics such as haloperidol moderate the positive symptoms of schizophrenia via blockade
of mesolimbic D2 receptors, they are not effective in all patients and poorly alleviate negative-cognitive
symptoms (Kinon and Lieberman, 1996). Furthermore, concomitant blockade of striatal and hypophyseal
populations of D2 sites provokes motor and endocrine extrapyramidal side effects, respectively
(Cunningham-Owens, 1996). In the design of improved antipsychotic agents (Meltzer, 1995), many recent
studies have focused on the following conceptual developments of this classic, “mesolimbic
dopaminergic/D2 hyperactivity” theory of schizophrenia (Brunello et al., 1995; Kinon and Lieberman,
1996). First, a reduced activity of dopaminergic path ways innervating frontal cortex (FCX) may contribute
to largely intractable, negative and cognitive symptoms (Knable and Weinberger, 1997; Parellada et al.,
1998). Second, D3 and D4 receptors, which are closely related to their D2 counterparts, may be involved
in the pathogenesis and management of schizophrenia (Levant, 1997; Wilson et al., 1998). Third, in
addition to dopaminergic transmission, a dysfunction of serotonergic and adrenergic networks may be
implicated in psychotic states and their management (Baldessarini et al., 1992; Nutt, 1994; Roth and
Meltzer, 1995).
Within this framework, the dibenzodiazepine clozapine has attracted considerable interest because it
preferentially reinforces mesocortical versus subcortical dopaminergic transmission, possesses marked
affinity for D4 receptors, and interacts with a diversity of serotonergic and adrenergic receptors (ARs;
Brunello et al., 1995; Meltzer, 1995; Josselin et al., 1997; Millan et al., 1998b; Wilson et al., 1998). These
distinctive actions of clozapine likely underlie its superior (“atypical”) clinical profile (Brunello et al., 1995).
Clozapine is, thus, efficacious in a proportion of patients refractory to neuroleptics, exerts antipsychotic
activity in the absence of extrapyramidal side effects, and may control negative-cognitive symptoms,
although its efficacy against primary negative symptoms is still debated (Brunello et al., 1995). Apart from
the potential importance of non-D2 dopaminergic receptors, several serotonergic and AR subtypes have
been implicated in the actions of clozapine. For example, the pronounced antagonist actions of clozapine
at 5-hydroxytryptamine (5-HT)2A receptors may permit antipsychotic efficacy in the relative absence of
extrapyramidal side effects (Roth and Meltzer, 1995; Schmidt et al., 1995). Adrenergic mechanisms, via
actions in the FCX and other corticolimbic loci, play an important role in the control of mood and cognition
(Arnsten, 1997; Coull et al., 1997). Furthermore, a perturbation of adrenergic transmission has been
related to positive crises, intensification of negativesymptoms, and the risk of relapse after the
discontinuation of treatment (Maes et al., 1993). Notably, clozapine displays antagonist properties at a1and a2-ARs (Baldessarini et al., 1992; Nutt, 1994; Blake et al., 1998; Elman et al., 1999). In this respect,
the following points deserve emphasis. First, psychostimulants, such as cocaine and amphetamine,
increase extracellular levels of norepinephrine (NE); correspondingly, activation of a1-ARs in both
mesolimbic structures and the FCX may be involved in their excitatory actions (Baldessarini et al., 1992;
Darracq et al., 1998). Second, blockade of a1-ARs preferentially suppresses mesolimbic versusnigrostriatal
dopaminergic transmission (Lane et al., 1990; Svensson et al., 1995). Third, antagonism of a1-ARs
facilitates thalamic gating of sensory input to the cortex, a process compromised in psychotic patients
(McCormick and Pape, 1995; Bakshi and Geyer, 1997). Fourth, blockade of inhibitory a2-AR heteroceptors
on terminals of dopaminergic fibers in FCX enhances mesocortical DA release (Gobert et al., 1998). Fifth,
combined treatment with the a2-AR antagonist idazoxan and the neuroleptic fluphenazine affords a
“clozapine-like” profile of antipsychotic activity (Litman et al., 1996), and a2-AR antagonist actions are
implicated in the functional actions of clozapine in humans (Nutt, 1994; Elman et al., 1999). Finally, a2-AR
antagonist properties limit extrapyramidal side effects (Kalkman et al., 1998) and contribute to an
improvement in mood (Nutt, 1994). From these considerations, the potential interest of antipsychotics
sharing the adrenergic receptorial profile of clozapine appears evident. However, the potent histaminic and
muscarinic actions of clozapine are accompanied by autonomic/ cardiovascular side effects, and its
conversion to a “netrenium” metabolite can provoke agranulocytosis (Cunningham-Owens, 1996). In this
light, the present (and accompanying) papers describe a novel, potential antipsychotic, S18327 (1-{2-[4(6- Fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin- 2-one), which is chemically distinct
from clozapine.
l