SDZ 220-581

Description: IC50 Value: N/A SDZ 220-581 ((S)-alpha-amino 2'chloro-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid) is a potent, competitive antagonist at the NMDA glutamate receptor subtype. in vitro: Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitiveNMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task [1]. in vivo: Administration of SDZ 220-581 or CGS 19755 was associated with a robust reduction in PPI, whereas L-701,324, 4-Cl-KYN or MLA failed to alter PPI [2]. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (< or = 1 hr) and a long duration (> or = 24 hr) of action [3]. Rats were pretreated with clozapine (0 or 5.0 mg/kg) or haloperidol (0 or 0.1 mg/kg), together with SDZ 220-581 (0 or 2.5 mg/kg), and tested. SDZ 220-581 and SDZ EAB-515 decreased PPI without affecting startle magnitude [4]. Clinical trial: N/A

The competitive NMDA receptor antagonist SDZ 220-581 reverses haloperidol-induced catalepsy in rats.[Pubmed:8957251]

Eur J Pharmacol. 1996 Oct 31;314(3):307-11.

The present studies investigated whether SDZ 220-581 ((S)-alpha-amino 2'chloro-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid), a potent, competitive antagonist at the NMDA glutamate receptor subtype, reversed haloperidol-induced catalepsy in rats, a widely used model of Parkinson's disease. SDZ 220-581 (0.32-3.2 mg/kg i.p.) dose- and time-dependently reduced the time spent in an abnormal position induced by haloperidol (1.0 mg/kg s.c.). Compared to other NMDA receptor antagonists the rank order of potency was MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) > SDZ 220-581 > SDZ EAA 494 (D-CPPene: (S)-(E)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid) > SDZ EAB 515 ((S)-alpha-amino-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid). Since it has been demonstrate that SDZ 220-581 counters the effects of L-dihydroxyphenylalanine (L-DOPA) on the motor disturbances of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-pre-treated primates, the results suggest that the reversal of haloperidol-induced catalepsy by competitive NMDA receptor antagonists may not be predictive of efficacy in other models of Parkinson's disease.

Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-D-aspartate receptor antagonists in rats.[Pubmed:9918570]

J Pharmacol Exp Ther. 1999 Feb;288(2):643-52.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Systemically administered competitive NMDA receptor antagonists do not disrupt PPI in rats, leading to speculation that these compounds might have use as neuroprotective agents without the risk of psychotomimetic side effects. The effects on sensorimotor gating and locomotor activity of competitive NMDA receptor antagonists that either penetrate (SDZ 220-581 and SDZ EAB-515) or poorly penetrate [SDZ EAA-494 (D-CPPene)] the blood-brain barrier were compared. Rats were treated with either SDZ 220-581 (0, 2.5, or 5.0 mg/kg) or SDZ EAB-515 (0, 3.0, 10.0, or 30.0 mg/kg) and tested for PPI and locomotor activity. Different rats were tested for PPI after either systemic (0, 0.5, 1.0, or 5.0 mg/kg) or intra-amygdala (0 or 1.0 microg/microl) administration of D-CPPene. Finally, rats were pretreated with clozapine (0 or 5.0 mg/kg) or haloperidol (0 or 0.1 mg/kg), together with SDZ 220-581 (0 or 2.5 mg/kg), and tested. SDZ 220-581 and SDZ EAB-515 decreased PPI without affecting startle magnitude. Reduced PPI was noted after central but not systemic administration of D-CPPene. The gating deficits produced by SDZ 220-581 were blocked by clozapine or haloperidol. Movement pattern analysis indicated that locomotor activity was increased by SDZ 220-581 and SDZ EAB-515 in a phencyclidine-like manner. These results indicate that competitive NMDA receptor antagonists, if they gain sufficient access to the brain, produce a behavioral profile that resembles that of the psychotomimetic noncompetitive antagonists.

Biphenyl-derivatives of 2-amino-7-phosphonoheptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonist--I. Pharmacological characterization in vitro.[Pubmed:8887974]

Neuropharmacology. 1996 Jun;35(6):643-54.

Omega-Phosphono-substituted alpha-amino acids have long been known to be antagonists at the N-methyl-D-aspartate (NMDA) receptor. D-2-Amino-5-phosphonopentanoic (D-AP5) and D-2-amino-7-phosphonoheptanoic (D-AP7) acids are the "prototype" compounds of this kind. Insertion of a biphenyl-moiety in the middle of the AP7 chain results in increased affinity and reverses the enantioselectivity from a D- to an L-form preference (Muller et al., (1992) Helv. Chim. Acta 75: 855-864). We describe here a series of substituted biphenyl-AP7-derivatives, the most potent of which have affinities (in a [3H]CGP-39653 binding assay using native and recombinant receptors) and potencies (antagonism of NMDA-induced depolarizations in a cortical wedge preparation; inhibition of glutamate-stimulated [3H]MK-801 binding under non-equilibrium conditions) in the low nanomolar range. Structure-activity relationships show that hydroxy-substitution at the C5-atom in the AP7-chain as well as substitution in the second phenyl ring with space filling (such as chloro-)groups in the para- and especially the ortho-position (extending the torsion angle of the two rings) increase affinity and potency of these compounds. They have no relevant affinities for the strychnine-insensitive glycine co-agonist site or the MK-801/PCP channel blocking site on the NMDA receptor complex. AMPA- and kainate-induced responses were not affected by biphenyl-analogues. These compounds also do not interact with a number of other neurotransmitter receptor sites, and they do not inhibit the uptake of [3H] glutamate in rat brain synaptosomes. However, they display affinities in the (sub)micromolar range for a non-NMDA, non-AMPA, non-kainate binding site for [3H]glutamate, measured in the presence of calcium chloride, the functional correlate of which has not yet been elucidated.

Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.[Pubmed:8887975]

Neuropharmacology. 1996 Jun;35(6):655-69.

A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.p. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (< or = 1 hr) and a long duration (> or = 24 hr) of action. Motor-debilitating effects (impairment of rotarod performance) occurred at doses about 10 times higher than those required for protection against MES. Neuroprotective activity was demonstrated by the ability of the compounds to reduce the extent of quinolinic acid-induced striatal lesions in rats, in the dose range of 3-15 mg/kg (i.p.) or 10-50 mg/kg (p.o.). In the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats, the test compounds reduced the infarct size by 40-50% when given i.v. before or by 20-30% when given i.v. 1 hr after MCAO. SDZ 220-581 provided 20-30% protection at > or = 2 x 10 mg/kg p.o. This compound also showed analgesic activity at low oral doses in a model of neuropathic pain, although higher doses were required in model of mechanical inflammatory hyperalgesia. Unexpectedly, SDZ 220-581 at low s.c. doses counteracted the antiparkinsonian effects of L-DOPA in MPTP-treated marmosets. (Sub)chronic administration of SDZ 220-581 did not reduce its ability to protect against quinolinic acid neurotoxicity, and no upregulation of NMDA receptors was detected using a [3H]CGP-39653 binding assay. In conclusion, from a series of biphenyl-AP7-derivatives, SDZ 220-581 is clearly the most active compound in vivo. Its pharmacological profile with a good, long-lasting oral activity might open up novel therapeutic applications for competitive NMDA receptor antagonists.