Locomotor activity detects subunit-selective effects of agonists and decahydroisoquinoline antagonists at AMPA/kainic acid ionotropic glutamate receptors in adult rats.

RATIONALE: In vitro studies have identified a series of decahydroisoquinoline compounds with differential selectivity for the subunits that comprise AMPA/kainic acid receptors. Compounds have been identified that have preferential activity at AMPA receptors (LY302679), whereas others (LY377770) have affinity for GluR5-kainic acid preferring subunit, which is activated by ATPA and kainic acid. OBJECTIVES: These studies set out to determine if locomotor activity could differentiate these profiles in vivo. METHODS: Locomotor activity was assessed in photocell drums in male Lister Hooded rats. RESULTS: AMPA, kainic acid and the GluR5 selective agonist ATPA, all suppressed spontaneous locomotor activity (SLA) in rats at doses of 1.0, 5.0 and 20 mg/kg resp. All three agonists achieve micromolar concentrations measured in whole brain after dosing with 10 mg/kg SC. The decahydroisoquinoline antagonist compounds, LY302679 (GluR2), LY293558 (GluR2, 5) and LY377770 (GluR5) all decreased SLA in rats (ED(min) 2.5, 5.0 and 20 mg/kg respectively). The rank order of potency at GluR2 subunits (LY302679>LY293558>LY377770) was reflected in the same rank order of activity for suppression of SLA. LY293558 reversed the suppression of SLA induced by all three agonists (0.62--2.5 mg/kg). LY377770 reversed the effects of ATPA only (ED(min) 1.0 mg/kg), LY302679 (ED(min) 2.5 mg/kg) attenuated the effect of kainic acid but was ineffective against AMPA and ATPA. CONCLUSIONS: Both agonist and antagonist suppression of SLA is associated with greater affinity for the GluR2 subunit, while compounds with affinity for the GluR5 subunit were less potent in suppressing SLA.

The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig.

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.

SAR development of a selective 5-HT1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis.

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.