ABSTRACT
On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Animals , Antidepressive Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme Inhibitors , Humans , Microdialysis , Piperazines/pharmacology , Quinolines/pharmacology , Rats , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Dopamine/metabolism , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.
Subject(s)
Fluoxetine/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Sexual Dysfunction, Physiological/chemically induced , Sexual Dysfunction, Physiological/prevention & control , Aminopyridines/pharmacology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Exploratory Behavior/drug effects , Female , Male , Olfactory Bulb/injuries , Olfactory Bulb/physiology , Ovariectomy , Piperazines/pharmacology , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Time FactorsABSTRACT
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Subject(s)
Cyclohexanols/chemistry , Ethylamines/chemistry , Ethylamines/pharmacology , Norepinephrine/metabolism , Symporters/antagonists & inhibitors , Animals , Cell Line , Ethylamines/therapeutic use , Female , Humans , Male , Mice , Models, Molecular , Molecular Structure , Pain/drug therapy , Rats , Structure-Activity Relationship , Symporters/metabolismABSTRACT
Structural modifications of the initial lead, 3-aminochroman (4), led to the identification of a novel series of pyridyl-fused amino chroman derivatives (5-8) and the structural isomers (9-12). The compounds described were evaluated for dual 5-HT transporter inhibitory and 5-HT(1A) receptor activities. The design strategy, synthesis, and in vitro biological characterization for these novel compounds are described.
Subject(s)
Chromans/chemistry , Chromans/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/drug effects , Animals , Humans , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesisABSTRACT
2,3-Dihydro-1,4-benzodioxanes with aryl 8-aza-bicyclo[3.2.1]oct-3-ene attachments 2 produce compounds with potent 5-HT-T affinity, and weak 5-HT(1A) affinity and alpha(1) affinity. This compares with 2,3-dihydro-1,4-benzodioxanes containing 8-aza-bicyclo[3.2.1] octan-3-ol attachments 4 which possess potent 5-HT(1A) affinity, moderate to good selectivity over alpha(1) and little 5-HT-T affinity. A 3-benzothiophene analogue of 4 (30) was synthesized which possesses potent 5-HT(1A) affinity and especially good selectivity over both alpha(1) and 5-HT-T.
