Aromatic analogs of arcaine inhibit MK-801 binding to the NMDA receptor

Sharma, Terre A.; Carr, Andrew; Davis, Rebecca S.; Reynolds, Ian J.; Hamilton, Andrew D.

doi:10.1016/s0960-894x(98)00631-3

Cited by 9 publications

(7 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the loss in potency after central introduction of N was not only equalized, but even reversed to a considerable gain, the aromatic residue may find a partner for favorable interaction in this middle part of the pharmacophore, as already suggested by previous studies. 41–43 Imidazoline instead of amidine substituents (as in 6 ) were not tolerated at this target, as already shown for other pentamidine derivatives. 44 …”

Section: Resultssupporting

confidence: 54%

“…Three others had aromatic rings inserted in ( 58 ) or attached to the bridge ( 13, 14 ), confirming earlier observations pointing to a role for such aromatic rings in target interaction. 41–43 Among analogs with shorter bridge, only 38 with 2 ethyl substituents was more potent than 1 (ANOVA, p <0.05). Ironically, the lead homopiperazine 24 stayed the only high-potency bisbenzamidine of this structural type; none of the other homopiperazines came close.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pentamidine analogs as inhibitors of [3H]MK-801 and [3H]ifenprodil binding to rat brain NMDA receptors

Berger

Maciejewska

Eynde

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [3H]MK-801 and the [3H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.

show abstract

Section: Resultssupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Pentamidine analogs as inhibitors of [3H]MK-801 and [3H]ifenprodil binding to rat brain NMDA receptors

Berger

Maciejewska

Eynde

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…It was ineffective in formalin and mechanical flexion reflex test but did not cause motor dysfunction at the highest dose studied [151]. Similar to agmatine, it is proposed to bind the open channel [215,216].…”

Section: Alkyl Guanidinesmentioning

confidence: 99%

N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

Brown¹,

Krupp²

2006

CTMC

View full text Add to dashboard Cite

NMDA receptors are known to be involved in nociceptive transmission and pain processing. Many structurally diverse NMDA antagonists have been reported to have activity in both animal models and clinical models of neuropathic pain. Untoward side effects such as ataxia and sedation have severely limited the clinical uses of this class of potential therapeutics. However, antagonists at the glycine-site, NR2B sites and weak-binding channel blockers have demonstrated an improved side effect profile in animal models of pain. These types of compounds may hold potential promise for future pain therapies. This review covers reported pain data surrounding representative examples of NMDA antagonists and provides a current assessment of potential clinical utility.

show abstract

“…20 Our results provide further evidence in support of the hypothesis that an aromatic moiety near the center of polyamine derivatives contributes to polyamine inverse agonism. 7,21 Substitution of the primary amino groups of SPD and SPM resulted in potent NMDA channel blockers (e.g., compounds 2c, 10c, and 11b) with low SPM-sensitivities; these compounds most likely act directly at the NMDA receptor associated ion channel. However, SPD derivatives with moieties at the central N 4 position (1c and 1z) exhibited pronounced sensitivity to SPM in their inhibition, suggesting their interaction with a polyamine-sensitive site of the NMDA receptor.…”

mentioning

confidence: 99%