Synthesis and antinociception properties of phencyclidine derivatives with modified aromatic or cycloalkyl rings and amino group
MONATSHEFTE FUR CHEMIE
Authors: Ahmadi, Abbas; Khalili, Mohsen; Barzin, Mahnaz; Pooladi, Mohsen; Bakhtiari, Fatemeh; Barjeste, Maede; Nahri-Niknafs, Babak
Abstract
Phencyclidine is an arylcyclohexylamine compound which has received a lot of investigative attention due to the complex spectrum of behaviours and its complicated interactions with the central nervous system. Phencyclidine administration may act as stimulant, depressant, hallucinogen, and analgesic depending on dose and tested species. In this study, new phenyl and thienyl analogues with specific affinity for the phencyclidine sites in NMDA receptors, dopamine uptake blocking, or both of them were synthesized. The acute and chronic pain properties of these compounds were studied using the tail immersion and formalin tests on mice and the results were compared with control and phencyclidine groups at a dose of 10 mg/kg. The outcomes indicated that all synthesized compounds showed better activities to decrease acute thermal and chemical, but not chronic pains. Also, these effects were more significant for phenyl (group 1) compared to thiophene (group 2) analogues, which is probably due to the higher affinity of group 1 for inhibition of dopamine reuptake compared to binding to the phencyclidine sites in NMDA receptors in this family. [GRAPHICS] .
Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats
PSYCHOPHARMACOLOGY
Authors: Savolainen, Katja; Ihalainen, Jouni; Jalkanen, Aaro J.; Forsberg, Markus M.
Abstract
RationaleSocial withdrawal is a core feature of the negative symptoms of schizophrenia. Currently available pharmacotherapies have only limited efficacy towards the negative symptoms, i.e., there is a significant unmet medical need in the treatment of these symptoms.ObjectiveWe wanted to confirm whether selective adrenergic (2C) receptor (AR) antagonist therapy could ameliorate acute phencyclidine (PCP)-induced schizophrenia-like social interaction deficits in rats, and to compare the effects of an (2C) AR antagonist to another putative therapeutic alternative, an (7) nicotinic acetylcholine receptor (nAChR) partial agonist, as well against three commonly used atypical antipsychotics.MethodsHere, we used acute PCP administration and modified a protocol for testing social interaction deficits in male Wistar rats and then used this model to compare the effects of an (2C) AR antagonist (ORM-13070 0.3 and 1.0mg/kgs.c.) with an (7) nAChR partial agonist (EVP-6124 0.3mg/kgs.c.) and three atypical antipsychotics (clozapine 2.5mg/kgi.p., risperidone 0.04 and 0.08mg/kgs.c., olanzapine 0.125 and 0.5mg/kgs.c.) on social interaction behavior.ResultsAcute PCP (1.5mg/kgs.c.) produced robust and reproducible deficits in social interaction behavior without affecting locomotor activity. The selective (2C) AR antagonist significantly ameliorated PCP-induced social interaction deficits. In contrast, neither the partial (7) nAChR agonist nor any of the three atypical antipsychotics were able to reverse the behavioral deficits at the selected doses.ConclusionOur findings confirm that (2C) AR antagonism is a potential mechanism for the treatment of the negative symptoms of schizophrenia.