Chemical Design of Peripherally Acting Compounds

Some guanidines, related in structure to mianserin and to 2-methyl-1,2,9,13b-tetrahydro-3H-dibenz[c,f]imadazo[1,5a] azepin-3-imine hydrobromide (WAL 801), have been synthesized and shown to be peripherally acting 5-HT2 antagonists. Structurally related compounds but not bearing a charged ionic group have been shown to have central activity. 2. Computer-aided molecular modelling has been used to establish a 5-HT2 pharmacophore. 3. The principle of exclusion from the CNS by incorporating a highly polar group to a biologically active molecule has been extended to the design and synthesis of a peripherally acting analgesic.