Lu 35-138 is a dual dopamine D4 receptor antagonist and serotonin reuptake inhibitor (SRI), among other actions, which was under development for the treatment of schizophrenia but was never marketed. Its route of administration is unspecified. The drug shows high affinity for the dopamine D4 receptor (Ki = 5 nM) and is a competitive antagonist of this receptor (Kb = 8 nM). In addition, it is a potent serotonin reuptake inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 3.2 nM. Subsequent research found that Lu 35-138 is a potent negative allosteric modulator or allosteric inhibitor of the serotonin transporter (SERT), with an IC50 of 43.8 nM in the later study. Lu 35-138 also shows affinity for the α1-adrenergic receptor (Ki = 45 nM). Its affinities for various other monoamine receptors have been reported as well, for instance at the dopamine D2 receptor (Ki = 72 nM; 14.4-fold lower than for the dopamine D4 receptor) and serotonin 5-HT2A receptor (Ki = 260 nM), with significant dopamine D2 receptor occupancy notably observed in vivo in rodents. In addition to its actions at monoaminergic targets, Lu 35-138 is a hERG blocker, with an IC50 of 270 nM. For comparison, haloperidol and sertindole had IC50 values for this action of 170 nM and 64 nM, respectively. Similarly to many antidepressants, Lu 35-138 produces antiaggressive effects acutely and proaggressive effects with chronic administration in rodents. It reverses the hyperlocomotion induced by dextroamphetamine and phencyclidine (PCP) in rodents. However, it was unable to affect the hyperlocomotion induced by a high dose of dextroamphetamine, which was said to reflect a preferential action on limbic versus striatal structures. The drug also reduced dextroamphetamine-induced disruption of prepulse inhibition. Continuous administration of Lu 35-138 reduced the number of spontaneously active dopaminergic neurons in the ventral tegmental area (VTA), which was said to be consistent with antipsychotic-like activity. Lu 35-138 did not produce catalepsy in rodents or dystonia in monkeys, suggesting low risk of extrapyramidal symptoms (EPS). Due to unfavorable physicochemical properties, the drug has been found to have very low oral bioavailability of less than 5% in rats. Lu 35-138 was first described in the scientific literature by 2002. It was under development by Lundbeck in Denmark. The drug reached phase 2 clinical trials for schizophrenia prior to the discontinuation of its development in December 2003.
See also Piperidinylindole List of investigational antipsychotics Sertindole Lu AF35700 (d8-zicronapine) Sonepiprazole
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