Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression.

A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.

[1]  Scott J. Miller,et al.  Bis(oxazoline)copper(II) complexes as chiral catalysts for the enantioselective Diels-Alder reaction , 1993 .

[2]  D. Grahame-Smith.  STUDIES IN VIVO ON THE RELATIONSHIP BETWEEN BRAIN TRYPTOPHAN, BRAIN 5‐HT SYNTHESIS AND HYPERACTIVITY IN RATS TREATED WITH A MONOAMINE OXIDASE INHIBITOR AND L‐TRYPTOPHAN , 1971, Journal of neurochemistry.

[3]  P. Masand,et al.  Psychostimulant augmentation of second generation antidepressants: A case series , 1998, Depression and anxiety.

[4]  V. S. Anand,et al.  Evaluating the tolerability of the newer antidepressants. , 1999, The Journal of nervous and mental disease.

[5]  M. Bourin,et al.  Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity , 1998, Psychopharmacology.

[6]  A. Puech,et al.  Antagonism of hypothermia and behavioral response to apomorphine: A simple, rapid and discriminating test for screening antidepressants and neuroleptics , 2004, Psychopharmacology.

[7]  I. Hachiya,et al.  Asymmetric Diels-Alder reaction catalyzed by a chiral ytterbium trifluoromethanesulfonate , 1993 .

[8]  Davidr . Evans,et al.  Asymmetric Diels-Alder cycloaddition reactions with chiral .alpha.,.beta.-unsaturated N-acyloxazolidinones , 1988 .

[9]  J. Nelson.  Augmentation strategies with serotonergic-noradrenergic combinations. , 1998, The Journal of clinical psychiatry.

[10]  C. Nemeroff,et al.  Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. , 1997, The Journal of pharmacology and experimental therapeutics.

[11]  I. Hindmarch.  Expanding the horizons of depression: beyond the monoamine hypothesis , 2001, Human psychopharmacology.

[12]  S. Childers,et al.  Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site. , 1996, Journal of medicinal chemistry.

[13]  R. H. Kline,et al.  Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. , 1997, Journal of medicinal chemistry.

[14]  K. Bogeso,et al.  3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake. , 1985, Journal of medicinal chemistry.

[15]  Davidr . Evans,et al.  New asymmetric Diels-Alder cycloaddition reactions. Chiral .alpha.,.beta.-unsaturated carboximides as practical chiral acrylate and crotonate dienophile synthons , 1984 .

[16]  R. Baldessarini,et al.  Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. , 1997, The Journal of clinical psychiatry.

[17]  R. Rosen,et al.  Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. , 1998, The Journal of clinical psychiatry.

[18]  Scott J. Miller,et al.  C2‐Symmetric Cationic Copper(II) Complexes as Chiral Lewis Acids: Counterion Effects in the Enantioselective Diels–Alder Reaction , 1995 .