Brain cannabinoid (CB(1)) receptors are G-protein coupled receptors and belong to the rhodopsin-like subfamily. A homology model of the inactive state of the CB(1) receptor was constructed using the x-ray structure of beta(2)-adrenergic receptor (beta(2)AR) as the template. We used 105 ns duration molecular-dynamics simulations of the CB(1) receptor embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer to gain some insight into the structure and function of the CB(1) receptor. As judged from the root mean-square deviations combined with the detailed structural analyses, the helical bundle of the CB(1) receptor appears to be fully converged in 50 ns of the simulation. The results reveal that the helical bundle structure of the CB(1) receptor maintains a topology quite similar to the x-ray structures of G-protein coupled receptors overall. It is also revealed that the CB(1) receptor is stabilized by the formation of extensive, water-mediated H-bond networks, aromatic stacking interactions, and receptor-lipid interactions within the helical core region. It is likely that these interactions, which are often specific to functional motifs, including the S(N)LAxAD, D(E)RY, CWxP, and NPxxY motifs, are the molecular constraints imposed on the inactive state of the CB(1) receptor. It appears that disruption of these specific interactions is necessary to release the molecular constraints to achieve a conformational change of the receptor suitable for G-protein activation.