Further Structural Exploration of Trisubstituted Asymmetric Pyran Derivatives (2S,4R,5R)-2-Benzhydryl-5-benzylamino-tetrahydropyran-4-ol and Their Corresponding Disubstituted (3S,6S) Pyran Derivatives: A Proposed Pharmacophore Model for High-Affinity Interaction with the Dopamine, Serotonin, and Norepinephrine Transporters Shijun Zhang, † Fernando Fernandez, † Stuart Hazeldine, † Jeffrey Deschamps, ‡ Juan Zhen, § Maarten E. A. Reith, § and Aloke K. Dutta* ,† Department of Pharmaceutical Sciences, Wayne State UniVersity, Detroit, Michigan 48202, Laboratory for the Structure of Matter, Code 6030, NaVal Research Laboratory, 4555 OVerlook AVenue SW, Washington, D.C. 20735, and New York UniVersity School of Medicine, Millhauser Laboratories Department of Psychiatry, New York, New York 10016 ReceiVed February 14, 2006 In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl- 5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the brain. In this report, we describe the further exploration of this series of molecules by incorporating functional groups in the molecular template, which should promote the formation of H bonds with the transporters. In addition, a new synthetic scheme for the asymmetric synthesis of disubstituted cis-(6-benzhydryl-tetrahydro- pyran-3-yl)-benzylamine analogues and their biological characterization is reported. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [ 3 H]- DA, [ 3 H]5-HT, and [ 3 H]NE, respectively. The compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [ 3 H]WIN 35, 428. The results indicated that the presence of functional groups, such as -OH, -NH 2 , and the bioisosteric 5-substituted indole moiety in both di and trisubstituted compounds, significantly increased their potencies for the SERT and NET, especially for the NET. Among the trisubstituted compounds, (-)-4b exhibited the highest potency for the NET and the SERT (K i of 2.13 and 15.3 nM, respectively) and was a serotonin norepinephrine reuptake inhibitor (SNRI). Compound (-)-4a exhibited the highest selectivity for the NET. Among the disubstituted compounds, a number of compounds, such as (-)-9a,(+)-9b,(-)-9b, and (+)-9d, exhibited significant low-nanomolar potencies for the SERT and the NET. Interestingly, compound (-)-9d exhibited appreciable potencies at all three transporters. On the basis of our present and past findings, we propose a qualitative model for the interaction of these compounds with monoamine transporters, which will be refined further in the future. Introduction Synaptic transmission involves the regulated release of neurotransmitters into the synaptic cleft for interaction with postsynaptic receptors. 1 The removal of biogenic amine trans- mitters from the cleft and from the extraneuronal space by their respective transporters enables the termination of the signal by its reuptake back into the presynaptic terminal, allowing a high constant level of neurotransmitters in the neuron and a low extraneuronal concentration. 2 Monoamine transporters, including the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET), play an important role in maintaining the concentration of biogenic amine neurotransmitters in the central nervous system (CNS). These transporters are involved in different pathological pro- cesses and have been implicated in many neurological disorders. 3-8 DAT is believed to be the main target for mediating cocaine’s reinforcing and behavioral effects, although several lines of evidence also implicate the involvement of the sero- tonergic system in some capacity. 9-12 It is believed that dysfunctional SERT and NET systems in the CNS play an important role in the etiology of depression. 13,14 Structurally diverse molecules have been developed for targeting monoamine transporter systems in search of medica- tions for various diseases such as cocaine addiction and depression. Especially, for the past one and half decades, the DAT has been a target for developing medications for cocaine addiction. In this respect, compounds with diverse structures have been developed as extensively reviewed in recent articles. 15-17 Similarly, various structurally different molecules have been developed for the inhibition of the SERT known as SSRIs, for example, fluoxetine (Figure 1). 18,19 SSRIs are known to possess pharmacological activity against depression and are used extensively as antidepressant agents. 19-21 However, selec- tive agents for the NET are relatively rare, compared to those for the DAT and the SERT. Recently, the highly selective NET blocker reboxetine (Figure 1) has been advanced for its strong antidepressant effect. 22-24 Compounds that are potent at both the SERT and the NET are known as SNRIs. Two well-known molecules belonging to the SNRI category are duloxetine and venlafaxine (Figure 1). 25 SNRIs such as venlafaxine exhibit antidepressant activity in clinical trials and produce a somewhat greater response and remission rates compared to those of SSRIs. 26 In our effort to design and discover novel templates for developing pharmacotherapies for cocaine addiction and other related neuro disorders, we recently developed 3,6-disubstituted and 2,4,5-trisubstituted tetrahydro-pyran derivatives targeting * Corresponding author. Tel: 313-577-1064. Fax: 313-577-2033. E- mail: adutta@wayne.edu. † Wayne State University. ‡ Naval Research Laboratory. § New York University School of Medicine. 4239 J. Med. Chem. 2006, 49, 4239-4247 10.1021/jm0601699 CCC: $33.50 © 2006 American Chemical Society Published on Web 06/16/2006