New polyamine-sensitive inhibitors of the NMDA receptor: syntheses and pharmacological evaluation.
Derivatives of 5-(4-aminobutyl)-2-thiophene-octylamine, a potent polyamine-sensitive inhibitor of the NMDA receptor, were synthesized and evaluated as inhibitors of [(3)H]MK-801 binding to rat brain membranes. Alkylations of the terminal amino groups reduced inhibitory potency; only incorporation of the amino group of the short 4-aminobutyl arm into a piperidine ring was tolerated. Substitution of the thiophene nucleus with methyl or ethyl, and its replacement by a benzene nucleus, was of minor influence. The corresponding diguanidines exhibited high potency independent of chain length, whereas their sensitivity to spermine was sharply dependent on chain length. Insertion of an amide bond into the long octylamine arm increased sensitivity to spermine and to Tris buffer. Our results indicate that spermine sensitivity of [(3)H]MK-801 binding inhibition is responsive to subtle changes in inhibitor structure and represents a promising target for pharmaceutical research.
Pöhler
Thomas
T
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Schadt
Oliver
O
Niepel
Daniela
D
Rebernik
Patrick
P
Berger
Michael L
ML
Noe
Christian R
CR
D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D013876:Thiophenes