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γ-hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog, trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modifications performed on HOCPCA led to reduced affinity. In contrast, introduction of diaromatic substituents into the 4-position of T-HCA led to high-affinity analogs (medium nanomolar Ki) for the GHB high-affinity binding sites as the most high-affinity analogs reported to date. The SAR data formed the basis for a 3-dimensional pharmacophore model for GHB ligands, which identified molecular features important for high-affinity binding, with high predictive validity. These findings will be valuable in the f...

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.

By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype, respectively. While the 5-HT6 ligands were antagonists, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits.

A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA(A) receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. The unsubstituted 4-AHP analogue (2a) (EC(50) 19 μM, R(max) 69%) was a moderately potent agonist at human α(1)β(2)γ(2) GABA(A) receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α(1)β(2)γ(2) GABA(A) receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP, 1). Selectivity for α(1)β(2)γ(2) over ρ(1) GABA(A) receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.

The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool. The excitatory amino acid transporters (EAATs) belong to the solute carrier family 1 (SLC1), and carry out the concentra- tive uptake of (S)-glutamate (Glu) (and aspartate (Asp)) from the glutamatergic synaptic cleft. 1-3 Five EAAT subtypes have been identified to date, in humans termed EAAT1-EAAT5. For historical reasons the nomenclature differs in rodents: the orthologues of human EAAT1, EAAT2 and EAAT3 subtypes are termed GLAST, GLT-1 and EAAC-1, respectively, whereas the nomenclature for EAAT4,5 is conserved across the species. The EAATs display differential localization and overall distribution patterns in the adult rodent brain. Whereas GLAST (EAAT1) and GLT-1 (EAAT2) are astroglial transporters, EAAC-1 (EAAT3) and EAAT4 are predominantly found in neurons. 4 GLT-1 (EAAT2) is the predominantly expressed subtype, found throughout the brain and spinal cord, and has been shown to be responsible for >90% of the Glu uptake in the adult brain. 4-6 GLAST (EAAT1) is found at the highest levels in the cerebellum with lower levels in the cortex and spinal cord, 7 and EAAC-1 (EAAT3) is expressed in high densities at postsynaptic terminals in the whole brain, particu- larly in the hippocampus, cerebellum, and basal ganglia. 4 EAAT4 is highly enriched in the Purkinje cells of the cerebel- lum, but the transporter has also been detected in the rat fore- and midbrain albeit in dramatically lower levels. 4,5,8,9 Finally, EAAT5 is found exclusively in the retina. 4,5,10 In agreement with the distribution and densities of the CNS subtypes, EAAT2 knockout mice have displayed pronounced loss of hippocampal neurons, seizures, and 50% mortality at 6 weeks of age. In contrast, knockout of GLAST (EAAT1), EAAC-1 (EAAT3), or EAAT4 in mice have been reported not to cause significant abnormalities in anatomy or in CNS-related phenotypes. 4,6 However, such studies may not be fully conclusive when it comes to elucidation of the physiological importance of the specific transporter subtype, as the absence of physiologic and phenotypic effects in the knockout mice may also be ascribed to compensatory mechanisms. Hence, we believe that valuable information about the physiological functions and thus thera- peutic potentials of a specific EAAT subtype may be addressed in a more subtle way by studying the actions of a selective ligand. 4