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.

PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor.

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.

Naphthyl piperazines with dual activity as 5-HT1D antagonists and 5-HT reuptake inhibitors.

SAR around a known molecule with dual 5-HT(1D) antagonist and 5-HT(transporter) inhibitory activity has led to the discovery of molecules with improved dual activity and reduced cross-reactivity toward other aminergic receptors (5-HT(1B), alpha(1), and D(2)).

Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter.

A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.

High affinity ligands for the alpha7 nicotinic receptor that show no cross-reactivity with the 5-HT3 receptor.

Potent and selective ligands of the alpha7 nicotinic acetylcholine receptor are required to understand the pharmacological effect of alpha7 activation. A common cross-reactivity occurs with serotonergic 5-HT3 receptors with which alpha7 receptors have a high sequence homology. We demonstrate that certain quinuclidine 3-biaryl carboxamides are high affinity alpha7 ligands with an excellent binding selectivity over 5-HT3 receptors.

1-Aryl-3,4-dihydro-1H-quinolin-2-one derivatives, novel and selective norepinephrine reuptake inhibitors.

A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion.

Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors.

Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.

Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives.

A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.

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.

Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression.

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.