4-phenylpiperazine derivatives with functionalized linkers as dopamine D3 receptor selective ligands and methods of use
Inventors
Newman, Amy Hauck • Grundt, Peter • Cyriac, George C. • Luedtke, Robert • Cao, Jianjing
Assignees
University of North Texas Health Science Center • US Department of Health and Human Services
Publication Number
US-8748608-B2
Publication Date
2014-06-10
Expiration Date
2027-06-15
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Abstract
Dopamine D3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D3 receptors and achieve high selectivity over D2 and D4 receptors.
Core Innovation
The invention relates to 4-phenylpiperazine derivatives with functionalized butylamide linking chains designed as dopamine D3 receptor selective ligands. By introducing functionality such as hydroxyl (OH) or acetate (OAc) groups into the linking chain of these ligands, the invention achieves improved D3 receptor affinity and selectivity, as well as enhanced water solubility. These modifications are well tolerated by D3 receptors and produce high selectivity over closely related dopamine D2 and D4 receptors.
The problem being addressed is the challenge in developing dopamine D3 receptor selective compounds due to the high amino acid homology between D2-like dopamine receptor subtypes, especially between D2 and D3 receptors. Existing compounds that achieve selectivity tend to be large molecules with highly lipophilic characteristics, leading to poor water solubility and low bioavailability. There is a recognized need for dopamine D3-selective compounds that penetrate the blood brain barrier effectively and show activity at relatively low dosages, overcoming metabolism and uptake challenges.
Claims Coverage
The patent contains several independent claims defining compounds characterized by their chemical structure and functionalized linking chains, reflecting multiple inventive features.
Chemical compound with a functionalized linking chain
The invention claims chemical compounds of a specified formula wherein the linking chain includes functional groups such as OH, OAc, alkoxy, halogen, amino, nitro, alkyl of 2-8 carbons, or pyridyl, conferring D3 receptor selectivity and improved pharmacological properties.
Specific substitutions on the linking chain and receptor binding moieties
Claims cover specific embodiments where the linking chain contains chiral centers at positions R3 or R4 substituted with OH or related groups, and where the moiety R5 is selected from phenyl, indole, thiophene, benzofuran, fluorenyl, or 2-pyridylphenyl, optionally substituted to enhance receptor selectivity and functional properties.
Compounds with particular stereochemistry
The claims include compounds with defined enantiomeric forms (R) or (S) at the hydroxy-substituted sites on the butyl amide linking chain, emphasizing control over chirality for receptor affinity and selectivity.
The claims collectively protect a range of 4-phenylpiperazine derivatives featuring functionalized linking chains with specific substituents and stereochemistry that provide improved dopamine D3 receptor affinity, selectivity, water solubility, and potential therapeutic utility.
Stated Advantages
Improved D3 receptor affinity and selectivity compared to previously known compounds.
Enhanced water solubility due to introduction of hydrophilic functional groups in the linking chain.
Improved bioavailability and CNS penetration as indicated by favorable cLogP and polar surface area values.
High selectivity over dopamine D2 and D4 receptors, reducing potential extrapyramidal side effects.
The compounds provide additional tools to study dopamine D3 receptor functions in vivo, especially related to drug reinforcement.
Documented Applications
Treatment of addictions including nicotine, alcohol, psychostimulant abuse such as cocaine and amphetamine.
Therapeutic use in schizophrenia, Parkinson's disease, and dyskinesias associated with these disorders.
Use as imaging probes for dopamine D3 receptors in the central nervous system for functional MRI, PET, or SPECT imaging.
Diagnosis and monitoring of neurodegenerative disorders characterized by abnormal D3 receptor distribution or density, such as Parkinson's disease.
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