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)).

A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.

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.

The whole cell variant of the patch-clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca2+ currents. The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3 and Lys-FTX-3.3 (synthetic analogues of FTX) were studied using cultured dorsal root ganglion neurones from neonatal rats, C2D7 cells (HEK293 cells stably coexpressing recombinant human N-type voltage-activated Ca2+ channel, α1B-1-α2bδβ1b subunits) and freshly isolated cerebellar Purkinje neurones. In dorsal root ganglion neurones, sFTX-3.3 (10 μM) inhibited high voltage-activated Ca2+ currents evoked by depolarisations to 0 mV from a holding potential of −90 mV. Partial overlap in Ca2+ current sensitivity to the polyamine sFTX-3.3 and the peptide spider toxin ω-Aga IVA was observed. However, evidence also suggests sFTX-3.3 and ω-Aga IVA do not show complete pharmacological overlap and that distinct parts of the Ca2+ current are sensitive to one of two inhibitors. The arginine group on sFTX-3.3 appears to be important for its inhibitory action on Ca2+ currents, because analogues where this amino acid was replaced with either ornithine (Orn-FTX-3.3) or lysine (Lys-FTX-3.3) were relatively inactive at concentrations below 1 mM. Synthesised FTX (100 μM) was inactive as an inhibitor of Ca2+ currents recorded from dorsal root ganglion and only produced modest effects in Purkinje neurones and C2D7 cells. At a concentration of 1 mM, nonselective actions were observed that indicated that synthesised FTX and sFTX-3.3 could reversibly inhibit both N- and P-type Ca2+ channels equally well. In conclusion, the potency of polyamines as nonselective inhibitors of Ca2+ channels is in part determined by the presence of a terminal arginine, and this may involve an interaction between terminal guanidino groups with Ca2+ binding sites.

A series of 2-thioether derivatives of a number of clavine alkaloid (ergoline) ring systems have been synthesized and tested for dopamine antagonist activity. Of the compounds tested 2-(methylthio)-agroclavine (8,9-didehydro-6,8-dimethyl-2-(methylthio)ergoline) (6) was the most potent and had a profile of activity in animal models indicative of potential antipsychotic activity. The synthesis and biological activity of a number of metabolites of 6, including the 13-hydroxy derivative, are also reported.

1. Toxins from invertebrates have proved useful tools for investigation of the properties of ion channels. In this study we describe the actions of arginine polyamine which is believed to be a close analogue of FTX, a polyamine isolated from the American funnel web spider, Agelenopsis aperta. 2. Voltage-activated Ca2+ currents and Ca(2+)-dependent Cl- currents recorded from rat cultured dorsal root ganglion neurones were reversibly inhibited by arginine polyamine (AP; 0.001 to 100 microM). Low voltage-activated T-type Ca2+ currents were significantly more sensitive to AP than high voltage-activated Ca2+ currents. The IC50 values for the actions of AP on low and high voltage-activated Ca2+ currents were 10 nM and 3 microM respectively. AP was equally effective in inhibiting high voltage-activated currents carried by Ba2+, Sr2+ or Ca2+. However, AP-induced inhibition of Ca2+ currents was attenuated by increasing the extracellular Ca2+ concentration from 2 mM to 10 mM. 3. The actions of AP on a Ca(2+)-independent K+ current were more complex, 1 microM AP enhanced this current but 10 microM AP had a dual action, initially enhancing but then inhibiting the K+ current. 4. gamma-Aminobutyric acid-activated Cl- currents were also reversibly inhibited by 1 to 10 microM AP. In contrast N-methyl-D-aspartate currents recorded from rat cultured cerebellar neurones were greatly enhanced by 10 microM AP. 5. We conclude that at a concentration of 10 nM, AP is a selective inhibitor of low threshold T-type voltage-activated Ca2+ currents. However, at higher concentrations 1-10 microM AP interacts with ion channels or other membrane constituents to produce a variety of actions on both voltage and ligand gated ion channels.

AbstractThe ambient carbanion derived from agroclavine (I) reacts with various electrophiles either at the 8‐ or 10‐position.