Pentiapine
[CAS# 81382-51-6]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: Pentiapine
• Synonyms: 5-(4-methylpiperazin-1-yl)imidazo[2,1-b][1,3,5]benzothiadiazepine
• Molecular Formula: C₁₅H₁₇N₅S
• Molecular Weight: 299.39
• CAS Registry Number: 81382-51-6
• SMILES: CN1CCN(CC1)C2=NC3=CC=CC=C3SC4=NC=CN24

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 548.2±60.0 °C 760 mmHg (Calc.)^*
• Flash point: 285.3±32.9 °C (Calc.)^*
• Index of refraction: 1.742 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovery and Applications

Pentiapine is a synthetic compound classified as an atypical antipsychotic, structurally and pharmacologically related to quetiapine. It belongs to the dibenzothiazepine class and was originally developed with the intention of modulating central nervous system neurotransmission by acting as an antagonist at various neurotransmitter receptors, notably dopamine D₂ and serotonin 5-HT_2A receptors. Like other antipsychotics in this category, pentiapine was intended to address symptoms of schizophrenia, including hallucinations, delusions, disorganized thinking, and affective disturbances.

Pentiapine was investigated during preclinical and early clinical development phases, primarily to evaluate its receptor binding profile, pharmacokinetics, and safety in comparison to existing antipsychotic agents. Its design was aimed at improving tolerability and minimizing extrapyramidal side effects commonly associated with first-generation antipsychotics, while retaining efficacy for both positive and negative symptoms of schizophrenia.

The pharmacodynamic properties of pentiapine showed that it binds with high affinity to 5-HT_2A and D₂ receptors, consistent with its intended mechanism as an antipsychotic. Additionally, pentiapine demonstrated some affinity for histamine H₁, adrenergic α₁, and muscarinic M₁ receptors, which are implicated in both therapeutic effects and side effects such as sedation, orthostatic hypotension, and anticholinergic symptoms. These receptor binding features are commonly observed in many second-generation antipsychotic drugs.

Despite promising early findings, pentiapine did not proceed to widespread clinical development or commercialization. The reasons for this may include suboptimal efficacy, unfavorable pharmacokinetics, or an adverse safety profile relative to other available agents. Because of its limited advancement, pentiapine has not been approved for clinical use by regulatory agencies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

In scientific literature, pentiapine is referenced primarily in the context of receptor binding studies or as a comparator compound in pharmacological research. It is sometimes included in structure-activity relationship (SAR) analyses exploring modifications to the dibenzothiazepine scaffold, aiming to better understand how structural changes affect receptor selectivity and functional activity. These studies contribute to the ongoing effort to develop new antipsychotic medications with improved therapeutic profiles.

While pentiapine has not achieved clinical relevance, its synthesis and investigation have provided useful information in the field of neuropsychopharmacology, particularly in understanding the design parameters of atypical antipsychotics. Its pharmacological characteristics offer insight into the balance between efficacy and side effects mediated by the complex interplay of receptor antagonism in the brain.

Pentiapine remains a compound of historical and academic interest in medicinal chemistry, particularly in the study of antipsychotic drug development. It exemplifies how numerous candidate molecules contribute to the scientific foundation, even if they do not reach the market as therapeutic agents.

References

1988. Presynaptic inhibition of nigrostriatal dopamine release in the mouse: Lack of cross tolerance between apomorphine, GBL and CGS 10746B. Life Sciences, 42(7).
DOI: 10.1016/0024-3205(88)90006-9

1993. Mono N-Aryl ethylenediamine and piperazine derivatives are GABAA receptor blockers: Implications for psychiatry. Neurochemical Research, 18(7).
DOI: 10.1007/bf00966774

2012. Role of the Dopaminergic System in the Acquisition, Expression and Reinstatement of MDMA-Induced Conditioned Place Preference in Adolescent Mice. PLoS ONE, 7(8).
DOI: 10.1371/journal.pone.0043107