MOLECULAR DETERMINANTS OF MU-RECEPTOR RECOGNITION FOR THE FENTANYL CLASS OF COMPOUNDS

We report here a theoretical study of a series of fentanyl analogs wit h a wide range of affinities and selectivities at the mu receptor, des igned to identify and characterize the molecular determinants of mu-re ceptor recognition. In this work, a complete conformational search com bining nested rotations and molecular dynamic simulations has been mad e, leading to identification of accessible conformers for all analogs and to the selection of a candidate bioactive form. In addition, elect ronic properties have been calculated and examined as possible modulat ors of recognition at the mu-receptor. The results of these studies ha ve led to a distinct pharmacophore for interaction at the mu receptor for this class of compounds, with the piperidine ring in a chair confo rmation and the N-phenethyl and 4-phenylpropanamide substituents both equatorial. Moreover, four key moieties necessary for optimum receptor recognition and a postulated role for each of them in this recognitio n have been identified. These are (i) a protonated amine nitrogen, ass umed to be involved in an initial electrostatic interaction with a neg atively charged site on the receptor; (ii) a polar function capable of hydrogen-bonding with an electrophilic site; (iii) an aromatic ring i nvolved in lipophilic interaction with a similar moiety; and (iv) a se cond aromatic ring, most probably involved in electron transfer intera ction with the receptor. These requirements, taken together, form the basis of our proposed mechanism for mu-receptor recognition. Not only is the presence of these component required for recognition, but speci fic steric relationships between them have been determined, implying t he appropriate arrangement for interaction with complementary receptor sites. These steric parameters are pseudobond angles and one torsion angle that determine the relative spatial arrangement of these four mo ieties. They are the angles theta(1) and theta(3), defining the relati ve position of the protonated nitrogen and the polar function with eac h of the two aromatic rings, and the torsion angle eta(1), defining th e orientation of the lone pair(s) on the polar proton-accepting functi on with respect to the lone pair on the piperidine nitrogen. This post ulated mechanism of recognition provides a conceptual framework to und erstand why some compounds do and some do not recognize the mu-recepto r.