A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin ~-H T~A and 5-HTz receptors by radioreceptor binding assays. They show high nanomolar affiiity for ~-H T~A , moderate affinity for D-2, and low affinity for 5-HTz receptors, and in particular, two compounds, 4-[3-( 1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyll-1-(2-methoxyphenyl)piperazine (8) and 4-[3-( 1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyll-l-(2-pyridyl)piperazine (E), show values (nM) of ICs0 = 2.0 and 1.4 for ~-H T~A and ICs0 = 90.6 and 119.3 for D-2, respectively.Some in vivo behavioral studies show compound 8 to be an antagonist on ~-H T~A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., and buspirone. 1-(2-methoxypheny1)-4-[4-(2-phthalimido)-n-butyl]piperazineCommon chlorpromazine-like antipsychotic drugs produce extrapyramidal symptoms (EPS), while antianxiety agents, such as benzodiazepines, present ataxia, sedative phenomena, and signs of drug dependence as side effects.Recent observationslJ indicate that improvement of these agents may be attained by combining dopaminergic and serotonergic activities in a single structure. Indeed, at the moment, there is considerable interest in molecules with multireceptorial activity3 as novel antipsychotic agents of potential clinical significance.Within this context, examples of compounds having both D-2 and 5-HTz receptor antagonist properties are setoperone4 and risperidone:b which have been evaluated in clinical trials, as well as new molecules which are predicted to be efficacious against negative symptoms of schizophrenia and to have fewer EPS.' Another example of an atypical neuroleptic drug with reduced side effects is clozapine which, in addition to acting on a specific subclass of dopamine receptors,8 interacts with significant affinity on a broad range of receptor types (serotonergic, adrenergic, muscarinic, a n d histaminergic).B-12Formerly, in our laboratories, we have synthesized compounds such as the l-aminoethylheterotetralin13J4 derivatives 1, which show no affinity for dopaminergic and serotonergic receptors, although they are open derivatives of active cyclic structures on DA and 5-HT receptors.In order to achieve this dual affinity for these receptors, we inserted the terminal nitrogen of the side chain of compounds 1 in an arylpiperazine structure. During the last decade, the arylpiperazine moiety has shown to be one of the templates for 5-HT activity,16 but minor Abstract published in Advance ACS Abstracts, December 15,1993. 1 : R --NE-2 : R --N 7 L N -Aryl modifications involve significant changes in affinity and selectivity, since it can also display moderate to high affinity for DA rece...

Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.

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