O

Me O

Me O

HYDANTOIN-BASED CBj RECEPTOR ANALOGUES

A series of 29 3-alkyl 5-arylimidazolidinones, or hydantoins, active at the CB1 receptor has been published by Kanyonyo et al. [344] with a subsequent publication describing the relationship between the experimentally derived lipophilicity and proposed modes of binding for non-polar and polar hydantoins derivatives [345] (Table 6.49).

The binding data for compounds (569)-(592) were obtained by screening at a concentration of 10 mM in a competitive displacement experiment using tritium-labelled (382) in CHO membranes transfected with the human CB1 receptor. Within the series, affinity was seen to improve as the alkyl chain length, and hence lipophilicity was increased. Compounds (588) and (589) were, however, surprisingly active for their calculated lipophilicity. The lip-ophilicity of the hydantoin analogues was measured by reverse-phase HPLC and found to correlate most closely with the values calculated by the CLIP [346] rather than CLOGP method [347]. In addition, ^ara-substitution of the two phenyl rings improved potency, with 5,5'-bis(4-bromophenyl) substitution, compounds (588)-(592), being optimal. For the non-polar hydantoins, the potency at the CB1 receptor decreased Br>OMe>F>Me>H, whereas no such relationship was evident for the non-polar compounds. Although certain polar groups, for example, morpholine (588) and hydroxyl (589) were well tolerated, the more basic amine group in compounds (570) and (571) had a strongly negative influence on binding. Molecular modelling studies comparing the hydantoins with the non-classical cannabinoid HHC utilised molecular lipophilic potential and hydogen bond potential to generate a superposition model. Two distinct binding modes, for polar and nonpolar hydantoins, were identified. The three most potent compounds (588), (589) and (591) were further characterised using a [35S]-GTPgS binding assay [348]. This assay allowed the test ligands to be defined as agonists (positive intrinsic activity), partial agonists (partial positive intrinsic activity), antagonist (no intrinsic activity) or inverse agonists (negative intrinsic activity). All three hydantoin ligands were found to behave as neutral

Table 6.49 3-ALKYL-5,5'-DIPHENYLIMIDAZOLIDINEDIONES - IN VITRO DATA

Cpd.

R1

R2

n

c log P"

% Displacement at 10 mMb

(569)

0 0

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