POLYAMINE ANALOG REGULATION OF NMDA MK-801 BINDING - A STRUCTURE-ACTIVITY STUDY

A series of analogues and homologues of spermine were synthesized, and their impact on MK-801 binding to the N-methyl-D-aspartate (NMDA) rec eptor was evaluated. These tetraamines encompass both linear and cycli c compounds. The linear molecules include norspermine, N-1,N-11-diethy lnorspermine, N-1,N-13-bis(2,2,2-trifluoroethyl)spermine, homospermine , and N-1,N-14-diethylhomospermine. The cyclic tetraamines consist of the piperidine analogues N-1-N-3-bis(4-piperidinyl)-1,3-diaminopropane , N-1,N-4-bis(4-piperidinyl)-1,4-diaminobutane, -1,N-4-bis(4-piperidin ylmethyl)-1,4-diaminobutane, and ,N-4-bis[2-(4-piperidinyl)ethyl]-1,4- diaminobutane and the pyridine analogues N-1-N-3-bis(4-pyridyl)-1,3-di aminopropane, N-1,N-4-bis(4-pyridyl)-1,4-diaminobutane, N-1,N-4-bis(4- pyridylmethyl)-1,4-diaminobutane, and -1,N-4-bis[2-(4-pyridyl)-ethyl]- 1,4-diaminobutane. This structure-activity set makes it possible to es tablish the importance of charge, intercharge distance, and terminal n itrogen substitution on polyamine-regulated MK-801 binding in the NMDA channel. Four families of tetraamines are included in this set: norsp ermines, spermines, homospermines, and tetraazaoctadecanes. Calculatio ns employing a SYBYL modeling program revealed that the distance betwe en terminal nitrogens ranges between 12.62 and 19.61 Angstrom. The tet raamines are constructed such that within families cyclics and acyclic s have similar lengths but different nitrogen pK(a)'s and thus differe nt protonation, or charge, states at physiological pH. The pK(a) value s-for all nitrogens of each molecule and its protonation state at phys iological pH are described. The modifications at the' terminal nitroge ns include introduction of ethyl and beta,beta,beta-trifluoroethyl gro ups and incorporation into piperidinyl or pyridyl systems. The studies clearly indicate that polyamine length, charge, and terminal nitrogen substitution have a significant effect on how the tetraamine regulate s MK-801 binding to the NMDA receptor. Thus a structure-activity basis set on which future design of MK-801 agonists and antagonists can be based is now available.