Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression
Abstract
The synthesis and SAR of a series of naphthyl containing chiral [2.2.1]bicycloalkanes as triple re-uptake inhibitors.
Introduction
Approaches to antidepressant therapy continue to be a significant area of central nervous system (CNS) research. Over the past 40 years monoamine re-uptake inhibition has been an important neuropharmacological strategy for the treatment of depression and in the modulation of mood.1, 2 The biogenic monoamines serotonin (5HT), norephinephrine (NE) and dopamine (DA) are amongst the most intensely studied of the 200+ chemical entities known to function as neurotransmitters in the mammalian CNS.
The use of selective serotonin re-uptake inhibitors (SSRIs) in the treatment of depression is well known, for example Prozac (fluoxetine 1). There are a number of issues with the use of SSRIs: latency of onset (typically 2–3 weeks), lack of efficacy (∼30% non-responders) and unwanted side effects such as sexual dysfunction, sleep disturbances, nausea, anxiety and reduced appetite. A newer strategy to address some of these issues has been the development of dual re-uptake inhibitors, a combination of 5HT and NE re-uptake inhibition (SNRIs), for example Efexor (venlafaxine 2) and Cymbalta (duloxetine 3).
Although DA dysfunction has been implicated in core depressive symptoms the potential of DA modulation in antidepressant therapy is less certain. A potential concern is the observation that drugs which act largely by blocking uptake of DA, for example Ritalin (methylphenidate 4) and cocaine 5 have a tendency to produce euphoria or dysphoria and psychomimetic effects.3 Others have found, for example, that the use of Bromocriptine (2-bromo-α-ergocryptine, an ergopeptine derivative and a DA agonist) and Wellbutrin (bupropion 6), which has DA re-uptake activity in vitro and in vivo, show antidepressant efficacy. Other combination studies4, 5, 6, 7, 8 have indicated that addition of some affinity at the DA uptake site may have some clinical benefit.
This paper describes our efforts to obtain compounds with equivalent functional activity at 5HT, NE and DA uptake sites, a triple re-uptake inhibitor. Our starting point was a historical series of Lilly compounds, trans-(7), cis-(8) and planar-(9) bicyclo[2.2.2]octanes. These compounds possess both NE and DA re-uptake inhibitor activity (Table 1).
We used pharmacophore models for each of the three re-uptake binding sites to visualise the relative spatial orientation of an aromatic moiety to a hydrophobe (bicyclo-rings) and to the amine. These models were built using the Catalyst™ modeling package in its common features approach.10 A training set from a combination of in-house and literature molecules having the basic structures described in Figure 1 and good activity for the appropriate binding site was formed.2, 10 The models predicted that the aryl group could be substituted aryl or bicycloaryl. Indeed, naphthyl had been shown by other workers11a–c to increase 5HT activity in a tropane series. The models could not be used to predict the influence of amine substituents. Each bicyclo system has cis, trans and planar isomers.
Both the bicyclo[2.2.1]heptanes and [3.2.1]octanes have endo and exo isomers and two stereogenic centres. With this in mind, we chose to focus our early efforts on the bicyclo[2.2.1]heptane series. This paper will describe the synthesis and SAR of a series of naphthyl bicyclo[2.2.1]heptanes. These derivatives were prepared by exploiting recent developments in asymmetric Diels–Alder reactions.
Section snippets
Chemistry
Compounds were prepared as described in Scheme 1 and associated catalyst details in Table 2. The requisite dienophiles 12 were prepared by N-acylation of oxazolidinones 11. The lithium salts of 11 were prepared by reaction with nBuLi and were then reacted with the mixed anhydride of acid 10, obtained by reaction with pivaloyl chloride, to afford 12. Treatment of achiral 12 (RH, Ar=3-ClC6H4) with cyclopentadiene at low temperature using Yb(OTf)312 as Lewis acid gave racemic cycloadducts 13 (
Results and discussion
Two principal in vitro tests were used to measure re-uptake activity of this series; binding affinity and synaptosomal uptake. The binding affinities were measured as inhibitory binding constants of the test drug against a known radiolabelled re-uptake inhibitor in a similar manner as for a postsynaptic agonist or antagonist. Synaptosomes are ‘pinched-off’ nerve terminals which contain much of the pre- and post-synaptic machinery intact. The ability of the test drug to inhibit the re-uptake of
Acknowledgments
The authors would like to thank both the Spectroscopy and Separation Sciences groups at Erl Wood for their invaluable contributions to this work. Thanks also to Magnus Walter for helping with the preparation of this manuscript.
References (23)
Hum. Psychopharmacol. Clin. Exp.
(2001)- et al.
J. Pharmacol. Exp. Ther.
(1997) - Baldessarini, R. J. Drugs and the Treatment of Psychiatic Disorders. In The Pharmacological Basis of Therapeutics, 7th...
J. Clin. Psychiatry
(1998)- et al.
Depression Anxiety
(1998) - et al.
J. Clin. Psychiatry
(1997) - et al.
J. Nervous Mental Dis.
(1999) - et al.
J. Clin. Psychiatry
(1998) - et al.
Biochem. Pharm.
(1978)
J. Med. Chem.
J. Med. Chem.
J. Med. Chem.
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Present address: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS.
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Present address: Bioreason, Chateau de l'Ile, Strasbourg, France.