Molecular modeling study of 4-phenylpiperazine and 4-phenyl-1,2,3,6-tetrahydropyridine derivatives: A new step towards the design of high-affinity 5-HT1A ligands

in Bioorganic & Medicinal Chemistry Letters (2010), 20(2), 1118-1123

The main feature of many drugs having a 5-HT1A affinity is the presence of an arylpiperazine moiety. Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered ... [more ▼]

The main feature of many drugs having a 5-HT1A affinity is the presence of an arylpiperazine moiety. Indeed, the protonated nitrogen and the aromatic ring of the arylpiperazine compounds are considered crucial for the interaction with the receptor. However, the replacement of the piperazine moiety by a 1,2,3,6-tetrahydropyridine ring in 4-arylpiperazine-ethyl carboxamide derivatives was recently shown to be highly favourable for 5-HT1A affinity. In order to better understand the favourable effect of this chemical modification, we performed a conformational analysis of these compounds mainly based on the position of the phenyl ring relative to the piperazine and tetrahydropyridine moiety. In the piperazine compounds, the phenyl ring preferentially adopts a perpendicular orientation, whereas an almost planar orientation seems to be the most favourable conformation for the tetrahydropyridine compounds. Therefore, this conformational difference appears as a key for a better interaction with the receptor binding site. This result will serve for the designing high-affinity 5-HT1A ligands. [less ▲]

Bis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)

in European Journal of Medicinal Chemistry (2010), 45

Molecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+ - activated K+ channel blockers

Poster (2008, May 30)

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in different parts of the brain. Activation of SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, hence reducing cell excitability. Blocking the SK channels might be beneficial for the treatment of depression, Parkinson’s disease and cognitive disorders. In this context, starting from the scaffold of N-methyl-laudanosine (NML) which is a known SK channel blocker (Scuvée-Moreau et al., 2002), a series of original bis-isoquinolinium derivatives were synthezised and evaluated for their affinity on the apamin-sensitive sites (Graulich et al., 2007). These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for SK channels than dequalinium. Based on a conformational analysis, a molecular modeling study was also performed. The heads of the various conformational families were compared to a pharmacophoric model previously described (Dilly et al., 2005). The in silico results are well correlated by the in vitro binding studies. Firstly, a 6,7-dimethoxy or a 6,7,8-trimethoxy substitution is shown to be favourable. Secondly, although the length of the linker has no significant influence in the alkane derivatives, the ortho and meta linkers lead to more favourable conformations than the para linker in the xylene derivatives. [less ▲]

Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.

in Current Medicinal Chemistry (2003), 10(8), 625-47

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2 ... [more ▼]

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability. [less ▲]