Lu 35-138

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.