Synthesis and Atypical Antipsychotic Profile of Some 2-(2-Piperidinoethyl)benzocycloalkanones as Analogs of Butyrophenone

Abstract

Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D1 receptors (Ki's in the micromolar range: 1.09-2.81) were slightly lower than that showed by haloperidol (Ki's in the nanomolar range: 5.01 and 97.72 for D2 and for D1 receptors, respectively). The ratio of pKi's values D1/D2 showed that the new molecules are more D2-selective than haloperidol. In contrast, in the [3H]-ketanserin binding assays the new compounds had greater affinity for 5-HT2A receptors (pKi's 7.89-8.60) than haloperidol (pKi 7.70) and in functional studies, endothelium-stripped aorta rings, the pA2 values (6.75-8.12) were slightly lower than that of ketanserin (8.87) in suppressing serotonin-induced contractions. The pKi's for D2 binding (and to a lesser extent pKi's for D1 binding) tend to be greater among typical (classical) than among atypical antipsychotics, while these two classes of antipsychotics exhibit no difference with regard to pKi's for 5-HT2A receptors. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds, and its potential induction of extrapyramidal symptoms (ratio values > 1.12 were predictive of an atypical antipsychotic profile). The new molecules had a ratio value in the range 1.08-1.20, while haloperidol showed a ratio of 0.93. In the behavioral screening tests, the new molecules showed antagonist activity of amphetamine-inducing hyperactivity and apomorphine-induced climbing (predictive tests for antipsychotic activity). In the catalepsy test (predictive test for induction of extrapyramidal symptoms), the values obtained were in accordance with an atypical antipsychotic drugs profile.

Synthesis and Benzodiazepine Receptor Affinity of Derivatives of the New Tricyclic Heteroaromatic System Pyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyridazin‐3(2H,5H)‐one

“…The structure of the new carboxylic derivatives was confirmed by analytical and spectral data. The 1 H-NMR spectra provided a basis for distinguishing among (E) and (Z) isomers (Table 1), in accordance with literature data reported for similar cycloalkylidene acetic acids [17,18]. The most important evidence for the different configuration of the double bond was the signal due to the exocyclic proton, which, for example, in the spectrum of 3a gave a singlet at 6.57 ppm (Z) and in the spectrum of 3b (E) a singlet significantly downfield-shifted (8.40 ppm) due to the deshielding effect of the conjugated carbonyl group at the 4-position ( Table 1).…”

Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1‐like receptors in neonatal rats

“…Ketanserin is a 5‐HT 2A/2C receptor antagonist (Hartman and Northup, 1996). In addition, the demonstrated affinities of LE300 and haloperidol to 5‐HT 2A receptors (Fontenla et al ., 1994; Seeman and Van Tol, 1994; Witt et al ., 2000; Rostom et al ., 2001; El‐Subbagh et al ., 2002) suggest that 5‐HT released by methamphetamine inhibits MSR via 5‐HT 2A receptors.…”

Synthesis of Functionalized Nitrogen Heterocycles by Radical Decarboxylation of β‐ and γ‐Amino Acids

“…Intense research has been devoted to the synthesis of functionalized piperidine and pyrrolidine rings, since these nitrogen heterocycles can be found in the structure of many natural products,1 synthetic drugs2 and chiral ligands or catalysts 3. For example, the ant defensive alkaloids (2 R )‐ and (2 S )‐solenopsin‐A ( 1 ; Figure 1),1a and the potent antipsychotic (±)‐haloperidol ( 2 )2a contain functionalized piperidine rings, while Corey’s catalyst 3 3a possesses a 2‐substituted pyrrolidine ring.…”