ABSTRACT
The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.
Subject(s)
Autoreceptors/physiology , Receptors, Presynaptic/physiology , Animals , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Chromatography, High Pressure Liquid/methods , Citalopram/pharmacology , Fluoxetine/pharmacology , Guinea Pigs , Hypothalamus/chemistry , Hypothalamus/drug effects , Hypothalamus/metabolism , Indoles/pharmacology , Male , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/pharmacology , Membrane Transport Proteins/metabolism , Membrane Transport Proteins/pharmacology , Microdialysis/methods , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/pharmacology , Piperidines/pharmacology , Piperidones/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Inbred Strains , Receptor, Serotonin, 5-HT1B/physiology , Receptor, Serotonin, 5-HT1D/physiology , Serotonin/metabolism , Serotonin/pharmacology , Serotonin 5-HT1 Receptor Agonists , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins , Species Specificity , Spiro Compounds/pharmacology , Subcellular Fractions/chemistry , Subcellular Fractions/pathology , Triazoles/pharmacology , Tritium , United KingdomABSTRACT
Incorporation of an SRI (serotonin reuptake inhibitor) pharmacophore into a selective 5-HT(1D) agonist has led to the discovery of a molecule having both 5-HT(1D) antagonist and SRI activity. RPS methodology was used to develop the SAR and identify potential approaches to reduce unwanted adrenergic alpha 1 and dopamine D(2) cross-reactivities.
Subject(s)
Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Cell Line , Cross Reactions , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Receptor, Serotonin, 5-HT1D/metabolism , Structure-Activity RelationshipABSTRACT
A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.
Subject(s)
Antidepressive Agents/chemistry , Bridged Bicyclo Compounds/chemistry , Depression/drug therapy , Neurotransmitter Uptake Inhibitors/chemistry , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/therapeutic use , Binding Sites/drug effects , Binding Sites/physiology , Bridged Bicyclo Compounds/metabolism , Bridged Bicyclo Compounds/therapeutic use , Depression/metabolism , Mice , Neurotransmitter Uptake Inhibitors/metabolism , Neurotransmitter Uptake Inhibitors/therapeutic use , Synaptosomes/drug effects , Synaptosomes/metabolismABSTRACT
5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP) and confirmed its activity on human recombinant alpha 7 receptors. However, PSAB-OFP also displayed high affinity binding to 5-HT(3) receptors. To assess the functional activity of PSAB-OFP on 5-HT(3) receptors we studied recombinant human 5-HT(3) receptors expressed in Xenopus oocytes, as well as native mouse 5-HT(3) receptors expressed in N1E-115 neuroblastoma cells, using whole-cell patch clamp and Ca(2+) imaging. Our results show that PSAB-OFP is an equipotent, partial agonist of both alpha 7 and 5-HT(3) receptors. We conclude that it will be necessary to identify the determinant of this overlapping pharmacology in order to develop more selective alpha 7 receptor ligands.
