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Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [ 3 H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal ⅐ mol Ϫ1 ), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (⌬H O ) and entropy (ϪT⌬S O )contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% ⌬G O ) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.Inhibitors of the serotonin transporter (SERT) have long been in clinical use for treatment of depression and anxiety, predating even the molecular identification of the target (Blakely et al., 1991). As such, SERT is the target of a large number of clinically proven drugs from diverse chemotypes (Fig. 1) that act by blocking transit of 5-hydroytryptamine (serotonin) (5-HT) through the transporter. Many reports describe the equilibrium binding properties of members of this class of drugs with SERT as well as potency for inhibition of 5-HT reuptake (Blakely et al., 1994;Tatsumi et al., 1997;Nemeroff and Owens, 2003;Rothman and Baumann, 2003). Although the three-dimensional structure of SERT has not yet been elucidated, crystal structures have been determined for other members of the 12 transmembrane domain major facilitator superfamily. Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al., 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al., 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors wer...

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PurposeTo describe two cases of differentiation syndrome presenting with ocular manifestations including bilateral chorioretinopathy in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and arsenic trioxide differentiation therapy.ObservationsThis observational case series identifies two patients at a single tertiary institution diagnosed with differentiation syndrome with associated ophthalmic involvement. Both patients reported bilateral reduction in visual acuity at days fourteen and ten respectively following initiation of differentiation therapy in addition to developing other systemic manifestations of differentiation syndrome. Both patients received the same chemotherapeutic regimen including both all-trans retinoic acid and arsenic trioxide as well as ten days of routine differentiation syndrome prophylaxis with oral prednisolone. Case 1 presented with bilateral pale yellow sub-retinal lesions concentrated at the posterior poles with ocular coherence tomography (OCT) evidence of bilateral multifocal areas of focal RPE elevation and adhesion to the thickened outer retina with interspersed sub-retinal fluid. Fluorescein angiography revealed areas of early hyperflouresence corresponding to the yellow chorioretinal lesions with late diffuse leakage of fluid into the subretinal space. Case 2 presented with a similar characteristic retinal findings on fundoscopy and optical coherence tomography. Both patients experienced rapid improvement in the visual symptoms and marked resolution of the sub-retinal fluid within seven to fourteen days of onset with excellent long-term visual outcome. Both patients achieved molecular remission after induction and received standard consolidation and maintenance therapy without visual disturbance.Conclusion and importanceOcular manifestations of differentiation syndrome have been only recently recognised. We present a case series of two patients with differentiation syndrome with ocular involvement. Common to both presentations was the presence of bilateral reduction in visual acuity with multifocal serous retinal detachment secondary to chorioretinopathy. The visual outcome from both presentations was excellent with rapid normalisation of visual acuity and resolution of the sub-retinal fluid with only the first case having their differentiation therapy temporarily withheld during the acute phase of illness.

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