Oxaprotiline

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Oxaprotiline
Oxaprotiline.svg
Systematic (IUPAC) name
(±)-3-(9,10-ethano-9,10-dihydro-9-anthryl)-1-methylamino-2-propanol
Clinical data
Legal status
  • Uncontrolled
Routes of
administration
Oral
Identifiers
CAS Registry Number 56433-44-4 N
PubChem CID: 38207
ChemSpider 35026 YesY
UNII 3V3Z2HK4LS YesY
ChEMBL CHEMBL1213009 YesY
Chemical data
Formula C20H23NO
Molecular mass 293.40 g/mol
 N (what is this?)  (verify)

Oxaprotiline (C 49-802 BDA), also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor of the tetracyclic antidepressant family that is related to maprotiline. Though investigated as an antidepressant,[1] it was never marketed.

Chemistry[edit]

Oxaprotiline is a racemic compound composed of two isomers, R(−)- or levo- oxaprotiline (levoprotiline; CGP-12,103-A), and S(+)- or dextro- oxaprotiline (dextroprotiline; CGP-12,104-A). Both enantiomers are active, with the levo- form acting merely as an antihistamine and the dextro- form having a more expansive pharmacology (see below), but with both unexpectedly still retaining antidepressant effects.[2]

Pharmacology[edit]

Dextroprotiline acts as a potent norepinephrine reuptake inhibitor[3][4] and H1 receptor antagonist,[5] as well as a very weak α1-adrenergic receptor antagonist.[3][6] It has negligible affinity for the serotonin transporter,[3] dopamine transporter, α2-adrenergic receptor,[3][6] and muscarinic acetylcholine receptors.[6] Whether it has any antagonistic effects on the 5-HT2 or D2 receptors like its relative maprotiline is unclear.

Levoprotiline acts as a selective H1 receptor antagonist, with no affinity for adrenaline, dopamine, muscarinic acetylcholine, or serotonin receptors, or any of the monoamine transporters.[3][4][5]

Synthesis[edit]

Several routes are available in patents for producing this agent.

Oxaprotiline synthesis:[7]

The first few steps leading to the key intermediate (1) parallel those for maprotiline starting with an acetic rather than a propionic acid. The carboxyl group is reduced to an aldehyde by sequential conversion to its acid chloride and then hydrogenation over a poisoned palladium catalyst. Reaction of the aldehyde with hydrogen cyanide leads to the corresponding cyanohydrin, which now incorporates the required third side chain carbon. Reduction with LAH yields the aminoalcohol. The primary amino group can then be monomethylated by any of several methods such as conversion to its carbamate followed by a second hydride reduction.

Acid chloride 1

See also[edit]

References[edit]

  1. ^ Giedke H; Gaertner H; Breyer-Pfaff U; Rein W; Axmann D (1986). "Amitriptyline and oxaprotiline in the treatment of hospitalized depressive patients. Clinical aspects, psychophysiology, and drug plasma levels". European archives of psychiatry and neurological sciences 235 (6): 329–338. doi:10.1007/bf00381001. PMID 3527706. 
  2. ^ Noguchi S, Fukuda Y, Inukai T (May 1992). "Possible contributory role of the central histaminergic system in the forced swimming model". Arzneimittel-Forschung 42 (5): 611–3. PMID 1530672. 
  3. ^ a b c d e Waldmeier PC, Baumann PA, Hauser K, Maitre L, Storni A (June 1982). "Oxaprotiline, a noradrenaline uptake inhibitor with an active and an inactive enantiomer". Biochemical Pharmacology 31 (12): 2169–76. doi:10.1016/0006-2952(82)90510-X. PMID 7115436. 
  4. ^ a b Reimann IW, Firkusny L, Antonin KH, Bieck PR (1993). "Oxaprotiline: enantioselective noradrenaline uptake inhibition indicated by intravenous amine pressor tests but not alpha 2-adrenoceptor binding to intact platelets in man". European Journal of Clinical Pharmacology 44 (1): 93–5. doi:10.1007/BF00315288. PMID 8382162. 
  5. ^ a b Noguchi S, Inukai T, Kuno T, Tanaka C (June 1992). "The suppression of olfactory bulbectomy-induced muricide by antidepressants and antihistamines via histamine H1 receptor blocking". Physiology & Behavior 51 (6): 1123–7. doi:10.1016/0031-9384(92)90297-F. PMID 1353628. 
  6. ^ a b c Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics 230 (1): 94–102. PMID 6086881. 
  7. ^ Wilhelm, M.; Bernasconi, R.; Storni, A.; Beck, D.; Schenker, K.; U.S. Patent 4,017,542 (1977).