Inverse agonists at the polyamine-sensitive modulatory site of the NMDA receptor: 50-fold increase in potency by insertion of an aromatic ring into an alkanediamine chain

• Published in: European journal of medicinal chemistry 1998, Vol.33 (1), p.3-14
• Main Authors: Berger, Michael L., Schödl, Clemens, Noe, Christian R.
• Format: Article
• Language: English
• Subjects: [ 3H]MK-801 binding; Biological and medical sciences; Glutamatergic system (aspartate and other excitatory aminoacids); Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NMDA receptor; Pharmacology. Drug treatments; polyamine; polyamine inverse agonist; thiophenedialkanamine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(99)80070-1

Polyamines like spermine and spermidine increase the opening frequency of the NMDA receptor associated ion channel and, as a consequence, specific binding of non-saturating concentrations of the channel radioligand [ 3H]MK-801. Compounds exhibiting the contrary effect have been described as polyamine inverse agonists, with 1,12-dodecanediamine (N-12-N) being one of the most specific ones (IC 50 16.5 μM). Here we describe the synthesis of a series of long-chain alkanediamines, with a thiophene nucleus inserted at various positions, and report the discovery of 5-(4-aminobutyl)-2-thiopheneoctanamine (N-4-T-8-N), which inhibited specific binding of [ 3H]MK-801 by 50% at 0.33 μM. In the presence of 100 μM of spermine, 4.0 μM N-4-T-8-N was necessary to achieve the same degree of inhibition. N-4-T-8-N is the most potent polyamine inverse agonist presently known and should be a useful tool to elucidate the physiological significance of the polyamine regulatory site of the NMDA receptor complex.