Application of the Bivalent Ligand Approach to the Design of Novel Dimeric Serotonin Reuptake Inhibitors

Abstract

Chemical modulation of the monoamine neurotransmitter systems involving dopamine (DA), serotonin (5-HT), and norepinephrine (NE) provides an important means to control certain neurological disorders such as depression, 1 anxiety, 2 alcoholism, 3 chronic pain, 4 eating disorders, 5 and obsessive compulsive disorders. 6 For example, a major pharmaceutical approach to the treatment of depression has come about through the development of agents that interfere with the primary mechanism of removal of 5-HT or NE from the synapse. 7 As the result, the selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) 8 and paroxetine (Paxil), 9 among others, have been developed for the treatment of depression and related psychological disorders. Despite these recent clinical developments, a detailed understanding of the structural factors that govern the potency and selectivity of ligands at the specific monoamine transporters is still evolving. During our efforts to discover ligands of possible use as medications, 10 we discovered a rather interesting aspect of the 5-HT transporter (SERT) structure activity relationships (SAR), namely that significant selectivity and potency can be achieved through the use of a bivalent ligand approach (Figure 1).The rationale for employing the bivalent ligand approach stems from the possibility that dimeric structures may be capable of bridging independent recognition sites on the transporters resulting in a thermodynamically more favorable binding interaction than the monovalent binding of two molecules. 11 As such proximal binding sites are likely to differ in their location for the three monoaminergic transporters the length of the linker connecting the two binding moieties could thus provide a means to finetune transporter selectivity profiles. Empirical support for such a possibility stems from the enhanced potency and selectivity reported for both bivalent narcotic antagonists containing the naltrexamine pharmacophore 12 and for serotonin-based bivalent 5-HT 1B/1D agonists. 13 We have recently reported on the chemistry and pharmacology of some 3,4-disubstituted piperidine-based ligands that show reasonable potency at the dopamine transporter (DAT). 14 On the basis of these and other studies 15 it had become apparent to us that 3,4-disubstituted piperidines are structurally related to drugs such as femoxetine and paroxetine that exhibit high potency and selectivity for the SERT. 16 One of these piperidines was therefore chosen as the starting monomer for the assembly of bivalent ligands that were postulated to exhibit potent and selective SERT activity.Briefly, piperidine-based ligands 4-16 were prepared in optically pure form from arecoline (1) 14 (Scheme 1) and were evaluated for their ability to inhibit high affinity uptake of DA, 5-HT, and NE using rat synaptosomal nerve endings. 17 The uptake data expressed as K i values and the selectivity profile (ratio of K i values) for these compounds are provided in Table 1. In general, all dimers (7-16) exhibit substantially ...

Agonistic and Antagonistic Bivalent Ligands for Serotonin and Dopamine Receptors Including their Transporters

“…7) [39,40]. Measurement of inhibition of SERT, DAT, and NET, respectively, revealed an interesting dependence of transporter inhibition potency on spacer length: Increasing the spacer length for the (+)-ligands gradually decreases the affinities for both NET and DAT.…”

“…In contrast to these transporters, the most potent inhibitor of SERT has a spacer of five methylene groups [40]. To a lesser extent, this is also the case for the (-)-enantiomers [39]. The (-)-series yielded potent and selective SERT inhibitors, whereas the (+)-series yielded mainly compounds with mixed SERT/DAT affinities.…”

Natural and Synthetic Biologically Active Dimeric Molecules: Anticancer Agents, Anti-HIV Agents, Steroid Derivatives and Opioid Antagonists

“…2) [1,4]. [1,4]. 3) [5], or to bind to HIV protease receptor which exists, in its active form, as a two-fold symmetric homodimer.…”

“…The pyrrolo[2,1-c] [1,4]benzodiazepine (39,PBD) antitumor antibiotics are a class of sequence selective DNA binding agents derived from the Streptomyces species [30]. The biological properties of this class of antitumor antibiotics are attributed to their ability to form covalent DNA adducts between the C11 position of the B-ring and the N2 amino group of a guanine base [31].…”

“…Kamal and co-workers further reported the synthesis of novel A-C8/C-C2-exo unsaturated alkoxyamido-linked pyrrolo[2,1-c] [1,4]benzodiazepine dimers [36]. The most interesting dimer 45b (a diimine dimer) showed significant binding affinity with a ∆T m value of 8.…”