Chemical design of peripherally acting compounds.
1. 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.
Jackson
W R
WR
Department of Chemistry, Monash University, Melbourne, Victoria, Australia.
Copp
F C
FC
Cullen
J D
JD
Guyett
F J
FJ
Rae
I D
ID
Robinson
A J
AJ
Pothoulackis
H
H
Serelis
A K
AK
Wong
M
M
D003198:Computer Simulation; D003984:Dibenzazepines / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008803:Mianserin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009294:Narcotics / Q000737:chemistry; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D003984:Dibenzazepines; D007093:Imidazoles; D009294:Narcotics; D012702:Serotonin Antagonists; D008803:Mianserin; C053090:epinastine