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Umespirone

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Anxiolytic and antipsychotic drug
Pharmaceutical compound
Umespirone
Clinical data
Routes of
administration 		By mouth
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
Elimination half-life Unknown but effects last much longer than other azapirones, up to 23 hours after a single dose in human clinical studies.[1]
Identifiers
  • 3-butyl-7-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetrone
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H40N4O5
Molar mass 512.651 g·mol−1
3D model (JSmol)
  • O=C1N(C(=O)C2C(=O)N(C(=O)C1C2(C)C)CCCCN4CCN(c3ccccc3OC)CC4)CCCC

Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties.[2] [3] [4] [5] It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM).[2] [6] [7] Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.[1] [5] [6]

Synthesis

[edit ]
Synthesis:[8] Patent:[9]

The condensation between ethyl cyanoacetate (1) and acetone gives ethylisopropylidenecyanoacetate [759-58-0] (2). This product is reacted with N-butylcyanoacetamide [39581-21-0] (3) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide, CID:10681941 (4). The glutarimide is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone, https://pubchem.ncbi.nlm.nih.gov/compound/10825633 CID:10825633 (5).

The reaction between 1-(o-anisyl)piperazine [35386-24-4] (6) and 1,4-dibromobutane [110-52-1] (7) gives the Quat salt CID:15895413(8).

Convergent synthesis (in the presence of potassium carbonate) affords Umespirone (KC-9172) (9).

See also

[edit ]

References

[edit ]
  1. ^ a b Holland RL, Wesnes K, Dietrich B (1994). "Single dose human pharmacology of umespirone". European Journal of Clinical Pharmacology. 46 (5): 461–8. doi:10.1007/bf00191912. PMID 7957544. S2CID 12117650.
  2. ^ a b Barnes NM, Costall B, Domeney AM, et al. (September 1991). "The effects of umespirone as a potential anxiolytic and antipsychotic agent". Pharmacology Biochemistry and Behavior. 40 (1): 89–96. doi:10.1016/0091-3057(91)90326-W. PMID 1685786. S2CID 9762359.
  3. ^ Ruhland M, Krähling H, Fuchs A, Schön U (November 1988). "KC 9172 (free base of KC 7218)--an antipsychotic/anxiolytic compound. I. Antipsychotic and anxiolytic activity in comparison with chlorpromazine, clozapine, diazepam and buspirone". Pharmacopsychiatry. 21 (6): 396–8. doi:10.1055/s-2007-1017024. PMID 2907649. S2CID 260241523.
  4. ^ Krähling H, Fuchs A, Ruhland M, Schön U, Mol F, Tulp M (November 1988). "KC 9172 (free base of KC 7218)--an antipsychotic/anxiolytic compound. II. Discrimination from typical neuroleptics and benzodiazepine-like minor tranquilizers". Pharmacopsychiatry. 21 (6): 399–401. doi:10.1055/s-2007-1017025. PMID 2907650. S2CID 260241655.
  5. ^ a b Schmidt WJ, Krähling H, Ruhland M (1991). "Antagonism of AP-5-induced sniffing stereotypy links umespirone to atypical antipsychotics". Life Sciences. 48 (6): 499–505. doi:10.1016/0024-3205(91)90464-M. PMID 1671523.
  6. ^ a b Ahlenius S, Wijkström A (November 1992). "Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat". European Journal of Pharmacology. 222 (1): 69–74. doi:10.1016/0014-2999(92)90464-F. PMID 1361441.
  7. ^ Itzhak Y, Ruhland M, Krähling H (February 1990). "Binding of umespirone to the sigma receptor: evidence for multiple affinity states". Neuropharmacology. 29 (2): 181–4. doi:10.1016/0028-3908(90)90058-Y . PMID 1970425. S2CID 54326248.
  8. ^ Kr鋒ling, H.; Krijzer, F. Drugs Fut 1991,16(5),437.
  9. ^ DE3529872 idem Uwe Schoen, Wolfgang Kehrbach, Werner Benson, Andreas Fuchs, Michael Ruhland, U.S. patent 4,771,044 (1988 to Kali-Chemie Pharma Gmbh).
Typical
Disputed
Atypical
Others
5-HT1AR Tooltip 5-HT1A receptor agonists
GABAAR Tooltip GABAA receptor PAMs Tooltip positive allosteric modulators
Hypnotics
Gabapentinoids
(α2δ VDCC blockers)
Antidepressants
Antipsychotics
Sympatholytics
(Antiadrenergics)
Others
SSRIs Tooltip Selective serotonin reuptake inhibitors
SNRIs Tooltip Serotonin–norepinephrine reuptake inhibitors
NRIs Tooltip Norepinephrine reuptake inhibitors
NDRIs Tooltip Norepinephrine–dopamine reuptake inhibitors
NaSSAs Tooltip Noradrenergic and specific serotonergic antidepressants
SARIs Tooltip Serotonin antagonist and reuptake inhibitors
SMS Tooltip Serotonin modulator and stimulators
Others
TCAs Tooltip Tricyclic antidepressants
TeCAs Tooltip Tetracyclic antidepressants
Others
Non-selective
MAOA Tooltip Monoamine oxidase A-selective
MAOB Tooltip Monoamine oxidase B-selective
Miscellaneous
α1
Agonists
Antagonists
α2
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β
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Antagonists
D1-like
Agonists
PAMs
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σ1
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5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
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5-HT2A
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5-HT2C
5-HT3 –7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
Simple piperazines
(no additional rings)
Phenylpiperazines
Benzylpiperazines
Diphenylalkylpiperazines
(benzhydrylalkylpiperazines)
Pyrimidinylpiperazines
Pyridinylpiperazines
Benzo(iso)thiazolyl piperazines
Tricyclics
(piperazine attached via side chain)
Others/Uncategorized


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