Dopamine and Serotonin - Drug Design and Discovery - page 304

tel udazine was at least 100 times more potent in these in vivo models. It was also shown that
tel udazine was an extremely potent and long-acting in vivo 5-HT 2 receptor antagonist (quipazine
model). Thus, tel udazine was a mixed D 2 and 5-HT 2 receptor compound.
During the 1980s, an electrophysiological in vivo model for the evaluation of limbic (linked to posi-
tive symptoms) versus striatal (linked to EPS) selectivity was introduced at Lundbeck. The model was
a chronic one where rats were treated with a compound for 3 weeks before the number of active dop-
amine neurons were counted in the VTA/SNC from where neurons project to limbic and striatal areas,
respectively. In this so-called VTA/SNC model treatment with classical antipsychotic drugs such as
chlorpromazine and haloperidol led to complete inhibition of neurons in both VTA and SNC by equal
doses, whereas clozapine selectively inactivated the dopamine neurons in the VTA. These results
corresponded to clinical data with regards to antipsychotic effect and EPS, and the model became of
key importance at Lundbeck as it had the potential to predict the therapeutic window between antipsy-
chotic effect and EPS of putative new antipsychotic drugs. It was subsequently shown that tel udazine
displayed some selectivity in this model predicting tel udazine to be atypical, but unfortunately, the
development of tel udazine was discontinued in Phase I due to toxicological i ndings in dogs.
It was also discovered that the removal of the “neuroleptic substituent” in the indane benzene ring
(i.e., the tril uoromethyl group in 18.19 ), reduced the D 2 receptor antagonism, whereas the 5-HT 2
receptor antagonism was retained. Concurrent replacement of the hydroxyethyl side chain with the
more bulky 1-ethyl-2-imidazolidinone side chain, resulted in irindalone ( 18.20 , Figure 18.3), which
was a very potent and selective 5-HT 2 antagonist. Irindalone was developed as a potential antihyper-
tensive drug, but the development was discontinued in Phase II in 1989 because of market consid-
erations. Irindalone was, in contrast to tel udazine, developed as the pure (1 R ,3 S )-enantiomer. This
coni guration of the 1-piperazino-3-phenylindanes is generally associated with receptor antagonistic
properties, whereas the (1 S ,3 R )- and the (1 R ,3 R )-enantiomers are NET/DAT reuptake inhibitors.
The piperazinoindanes are chiral molecules, which at that time complicated many stages of drug
discovery and development processes. Therefore, the corresponding piperazino-, tetrahydropyridino-,
and piperidino-indoles were designed, and it was discovered that the piperidinoindole moiety bioisos-
terically substituted for the trans -piperazinoindane with respect to D 2 and 5-HT 2 antagonism. One of the
compounds synthesized in this series was sertindole ( 18.16 , Figure 18.2), which incorporates structural
elements from both tel udazine (neuroleptic substituent) and irindalone (imidazolidinone side chain).
Despite high afi nity for both D 2 and 5-HT 2 receptors, sertindole displayed an in vivo proi le of a selec-
tive 5-HT 2 receptor antagonist. Therefore, it was surprising that sertindole in the VTA/SNC model
displayed a more than 100-fold selectivity for inhibition of dopamine neurons in the VTA as compared
to the SNC. Sertindole was subsequently pushed through development and marketed in 1996 for the
treatment of schizophrenia. Sertindole was temporarily withdrawn from the market in 1998 because of
uncertainties regarding the relation between QT prolongation and the ability to induce potentially fatal
cardiac arrhythmias in humans. However, the suspension of sertindole was lifted in 2002, and in January
2006, Estonia became the i rst country to reintroduce it. Sertindole is currently being introduced in sev-
eral European, Asian, Latin American and the USA. Interestingly, recent preclinical evidence suggests
sertindole being effective in the treatment of cognitive impairment in schizophrenia, with superiority
over other antipsychotics such as risperidone, olanzapine, and clozapine. The effect has putatively been
linked to potent 5-HT 6 receptor antagonism combined with lack of antimuscarinic activity. It is cur-
rently being investigated whether the preclinical i nding can be coni rmed in clinical trials.
18.3 TRANSPORTERLIGANDS
18.3.1 A NTIDEPRESSANT D RUGS
Antidepressant drugs represent ligands that target DAT, SERT, and NET to various degrees, and these
include i rst generation antidepressants (i.e., tricyclic antidepressants, TCAs), selective serotonin
reuptake inhibitors (SSRIs), combined serotonin and norepinephrine reuptake inhibitors (SNRIs),
and the more recently introduced allosteric serotonin reuptake inhibitor (ASRI), escitalopram.