Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

Histamine H-3 receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional histamine H-3 pharmacophore. The 4-(3-piperidinopropoxy) phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift af. nity at dopamine D-2- like receptors (D-2 and D-3), to decrease af. nity at histamine H-1 receptors, and to obtain H3R ligands with low nanomolar or subnanomolar af. nity. Change of effects at D-1-like receptors (D-1 and D-5) were heterogeneous. With these newly pro. led compounds different antipsychotic properties might be achieved. (C) 2008 Elsevier Ltd. All rights reserved.