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The electrophilic addition of reagents to the 5,6-double bond in spinosyn A and spinosyn D systems occurred with high pi-diastereofacial selectivity. Addition occurred preferentially from the beta face of the molecule with selectivities ranging from 5:1 to better than 30:1. Various NMR properties were investigated in order to distinguish the beta and alpha isomers with the help of theoretical models of the products. These NMR properties include a (13)C gamma effect to C-11 and vicinal coupling between H-4 and H-5. To help rationalize the selectivity, computational studies on the transition states for epoxidation were calculated using density functional theory. The results indicate that beta epoxidation is favored and that the geometries of the transition structures are consistent with torsional steering being the source of the selectivity.

In an effort to increase the insecticidal activity of the spinosyn family of naturally occurring macrolides, the 2'-, 3'- and 4'-O-desmethyl-O-acetyl analogs and the 2'-, 3'-, and 4'-O-desmethoxy analogs have been synthesized. These analogs were prepared synthetically from the minor spinosyn factors H, J, K, L and Q either via direct acylation of the corresponding factor or deoxygenation of an intermediate xanthate. The acylated analogs were all more potent insecticides against Heliothis virescens larvae than their respective parent factors, but not as potent as spinosyns A or D. The deoxy analogs were also more potent insecticides than their respective parent factors. The 2'-desmethoxy analogs showed, for the first time, analogs with insecticidal potency against H. virescens greater than that of spinosyns A and D, indicating that polarity is not well tolerated in the rhamnose moiety of spinosyn A.

Forosamine at the 17-position of spinosyns A and D was hydrolyzed under mild acidic conditions to give the corresponding 17-pseudoaglycones. The tri-O-methylrhamnose at the 9-position of the 17-pseudoaglycone of spinosyn A was hydrolyzed under more vigorous acidic conditions to give the aglycone of spinosyn A. However, these conditions led to decomposition of the 17-pseudoaglycone of spinosyn D, presumably due to more facile protonation of the 5,6-double bond to produce a tertiary carbonium ion which undergoes further rearrangements. Spinosyns J and L (3'-O-demethyl spinosyn A and D, respectively) obtained from fermentation of biosynthetically-blocked mutant strains of Saccharopolyspora spinosa, were oxidized to give the corresponding 3'-keto-derivatives and the resultant keto-sugars were then beta-eliminated under basic conditions to give the 9-pseudoaglycones of spinosyns A and D respectively. Forosamine at the 17-position of the 9-pseudoaglycone of spinosyn D was then readily hydrolyzed to yield the aglycone of spinosyn D.

Tazofelone is a new inflammatory bowel disease agent. The biotransformation of tazofelone in human livers and the cytochrome P450 responsible for the biotransformation has been studied. Two metabolites of tazofelone were formed in vitro. A sulfoxide metabolite was identified by cochromatography with authentic standards, and a quinol metabolite of tazofelone was identified by mass spectrometry and proton NMR. Sulfoxidation was catalyzed by a single enzyme system while formation of the quinol metabolite was catalyzed by a two enzyme system. The Km and Vmax values for sulfoxidation were 12.4 microM and 0.27 nmol/min/mg protein, respectively. The high affinity Km and Vmax values for the formation of the quinol metabolite were 7.5 microM and 0.17 nmol/min/mg protein, respectively. Tazofelone was incubated at 20 microM concentration with human microsomes to determine which of the cytochrome P450 isozyme(s) is involved in the oxidation of tazofelone. A strong correlation was found between the immunoquantified concentrations of CYP3A and the rates of formation of the sulfoxide and quinol metabolites of tazofelone. Similarly, significant correlations were observed between the formation of midazolam 1'-hydroxylation and the rates of formation of both metabolites of tazofelone. Inhibition studies have indicated that triacetyloleandomycin, a CYP3A specific inhibitor, almost completely inhibited the formation of both of these tazofelone metabolites. Incubations with specific cDNA expressed microsomes indicated that the formation of both the sulfoxide and quinol metabolites was highest with CYP3A4 containing microsomes. The correlation data was confirmed by inhibition studies and cDNA expressed cytochrome P450 systems demonstrating that the biotransformation of tazofelone to its metabolites is primarily mediated by CYP3A.

The lactone rings of the polyketides platenolide and tylactone are synthesized by condensation of acetate-, proprionate-, and butyrate-derived precursors. A hybrid tylactone/platenolide synthase was constructed to determine if the choice of substrate is programmed by the polyketide synthase and to ascertain if a substrate different than that normally used in the first step of platenolide synthesis could be incorporated into the final polyketide. In this work, we report the successful incorporation of a propionate in place of the acetate normally used in the first step of platenolide synthesis. This result demonstrates that polyketide synthases choose a particular substrate at defined steps and provides strong evidence that substrate choice is programmed by the acyl transferase domain of a large, multifunctional polyketide synthase.

The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

Ossamycin is a cytotoxic agent of undetermined structure that was originally isolated in 1965 from culture broths of Streptomyces hygroscopicus var. ossamyceticus. Its overall structure and relative stereochemistry have now been determined by single crystal X-ray diffraction studies. Absolute stereochemistry was established according to the previously determined configuration of its aminosaccharide constituent, ossamine. The aglycone of ossamycin possesses a 24-membered macrolide ring system onto which is incorporated both a 6,6-spiroketal and 5-membered hemiketal ring system. The overall three-dimensional structure possesses features in common with the related macrocyclic antibiotics dunaimycin, cytovaricin, and A82548A.

In our continuing effort to design novel thrombin inhibitors, a series of conformationally constrained amino acids (e.g. alpha-alkyl, N-alkyl cyclic, etc.) were utilized in a systematic structure-activity study of the P3, P2, and P1 positions of tripeptide arginal thrombin inhibitors. Early examples of this effort include: D-MePhe-Pro-Arg-H (15), Boc-D-Phg-Pro-Arg-H (18), D-1-Tiq-Pro-Arg-H (23, D-1-Tiq = D-1,2,3,4-tetrahydroisoquinolin-1-ylcarbonyl), and Boc-D-Phe-Pro-Arg-H (25).10a,20 The current work clarifies the contribution of each residue of the tripeptide arginals toward the potent and selective inhibition of thrombin relative to that of t-PA and plasmin. The alpha-methylarginal modification in the P1 residue resulted in analogs 30 (D-MePhe at P3) and 32 (D-1-Tiq at P3) which had lower potency toward thrombin while exhibiting improved selectivity. Analogs modified at the P2 site were found to be very sensitive to the conformational changes induced by variations in side chain ring size with the flexible pipecolinic acid 31 being 2 orders of magnitude less potent at thrombin inhibition than the conformationally constrained azetidine analog 20. Examination of the P3 binding region indicated that alpha-alkylphenylglycine residues resulted in a tendency to exhibit substantial improvements in selectivity over the nonalkylated residues. Combinations of optimal P3 and P2 changes led to compounds TFA-D-Phg(alpha Et)-Azt-Arg-H (16), TFA-D-Phg(alpha Me)-Azt-Arg-H (17), Ac-D-Phg(alpha Me)-Azt-Arg-H (21), TFA-D-Phg(alpha Me)-Pro-Arg-H (27), 30, and 32, which are clearly more selective for thrombin versus plasmin than the nonconformationally constrained compounds.

A new member of the spiroketal-containing macrolide class of fermentation-derived natural products was isolated from mycelial extracts of Streptomyces diastatochromogenes. The principal component, A82548A, was shown to possess a 22-membered macrolide ring system onto which was incorporated both a spiroketal and a hemiketal moiety. Relative stereochemistry was established by single crystal X-ray diffraction studies. Absolute stereochemistry was determined via hydrolysis of the amino sugar glycosidically linked to the aglycone, which was identified as L-kedarosamine. The overall three-dimensional structure is closely related to that of the macrolides cytovaricin, rutamycin, and ossamycin.

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyethoxymethyl substituent on the oxazine ring possesses the R configuration. Epidirithromycin is its isomer in which the methoxyethoxymethyl substituent has the opposite (S) configuration. Both compounds readily epimerize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent. An enriched sample of epidirithromycin (95% purity) was synthesized by condensing erythromycylamine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the reaction solvent, and the product was fully characterized by nuclear magnetic resonance spectroscopy and high-pressure liquid chromatographic (HPLC) analysis. Both oxazine derivatives readily hydrolyze to erythromycylamine, so all three compounds exhibit the same antibiotic activity in vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to erythromycylmine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, as measured by analytical HPLC in parallel experiments. Under these particular conditions, inhibition of ribosomal protein synthesis by dirithromycin was < 10% of the value measured for erythromycylamine.

The aqueous degradation of the carbacephalosporin loracarbef under moderately acidic conditions (pH range, 2.7-4.3) is described. Structures of a total of 10 compounds isolated by preparative reversed-phase HPLC have been proposed. Five of these 10 degradation compounds arose from hydrolysis of the beta-lactam ring followed by structural changes in the six-membered heterocyclic ring. Four compounds form from intermolecular reactions of loracarbef to form dimeric structures with peptide linkages. The remaining compound resulted from oxidation of the primary amine to a hydroxylamine. Pathways for the formation of these compounds from the parent loracarbef are proposed.

We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([3H]CGS19755, [3H]AMPA, and [3H]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [3H]CGS19755 binding with IC50S of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50S of 0.15 +/- 0.01 and 1.39 +/- 0.29 microM, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.

The biosynthetic origin of antibiotic A10255 was investigated using 14C- and 13C-labeled amino acids. DL-[1-(13)C]Serine labeled 15 of the 17 amino acid residues present in A10255G. These included the oxazole, thiazole, dehydroalanine, masked glycine, masked alanine and pyridine moieties. The same 15 residues labeled by serine were labeled by [2-(13)C]glycine, apparently by conversion of the glycine to [2,3-(13)C]serine. Formation of the pyridine ring occurred via a C3 to C3 condensation of two serines. The results indicated origin of the masked alanine from alanine; the masked glycine from glycine; the thiazole residues from cysteine; and the threonine, masked dehydrobutyrine, masked dehydronorvaline and masked dehydroleucine residues from threonine. L(-)[CH3-(13)C]Methionine labeled the methyl carbon of the masked dehydronorvaline moiety in factor B and the two methyl carbons of the masked dehydroleucine moiety in factor E. The results demonstrate that A10255 originates exclusively from amino acids in a manner similar to the closely related thiopeptide antibiotics nosiheptide and thiostrepton.

Dirithromycin is a 9-N-11-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.

We have prepared a series of cis-4-(tetrazolylakyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays [( 3H]CGS-19755, [3H]AMPA, and [3H]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [3H]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4 microM. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.

A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antimicrobial activity in vitro and in vivo, especially when administered orally to treat experimental infections in mice. From structure-activity studies, 9-N-(1-propyl)erythromycylamine (LY281389) was selected as the most efficacious derivative. These methods have also been extended to the synthesis of some 9-N,N-dialkyl derivatives of erythromycylamine.

Three branched-chain fatty acids (7-hydroxy-4,6-dimethylnona-2,4-dienoic acid [compound 1], its 7-epimer [compound 2], and 7-keto-4,6-dimethylnona-2,4-dienoic acid [compound 3]) and a ketone (9-hydroxy-6,8-dimethylundeca-4,6-dien-3-one [compound 4]) were isolated from the culture broth of mutants of Streptomyces fradiae which were blocked in the biosynthesis of the macrolide antibiotic tylosin. Two phenotypic classes of mutants of this organism which were blocked in the addition of mycaminose to tylactone (compound 6) accumulated these compounds. These compounds were not produced by mutants which were blocked in lactone synthesis, in steps beyond mycaminose addition, or by the wild-type strain. Synthesis of these compounds, like synthesis of tylosin, was inhibited by the addition of cerulenin. Compounds 1, 2, and 3 were partially interconvertible by these mutants; but they were not produced from the degradation of tylactone and they were not directly incorporated into tylosin by intact cells. The structures of compounds 1 and 2 were equivalent to that of a predicted intermediate (S. Yue, J. S. Duncan, Y. Yamamoto, and C. R. Hutchinson, J. Am. Chem. Soc. 109:1253-1255, 1987) in the biosynthesis of tylactone. The ketone (compound 4) reported previously (N. D. Jones, M. O. Chaney, H. A. Kirst, G. M. Wild, R. H. Baltz, R. L. Hamill, and J. W. Paschal, J. Antibiot. 35:420-425, 1982) appears to be the decarboxylation product of the intermediate following that represented by compound 1. This represents the first report of the isolation of putative precursors of tylactone from tylosin-producing organisms.

The structure of the novel nucleoside antibiotic A201A has been determined by a combination of chemical and spectroscopic methods. It is composed of 6-dimethylaminopurine, 3-amino-3-deoxyribose, p-hydroxy-alpha-methylcinnamic acid, a novel unsaturated hexofuranose and 3,4-di-O-methylrhamnose. Structures have also been assigned to several related minor factors simultaneously isolated from the fermentation broth. These unique nucleosides have very interesting similarities and differences in structure with the known antibiotics puromycin and hygromycin A.

5-O-Mycarosyltylactone has been isolated as a predominant factor from fermentation broths of a Streptomyces fradiae mutant. The relative configurations of mycarose and tylactone (protylonolide) have been determined by X-ray crystal structure analysis. Hydrolysis of 5-O-mycarosyltylactone yielded (-)-tylactone and L-(-)-mycarose. Taken together, these two experiments establish the absolute configuration of (-)-tylactone. Bioconversion of (-)-tylactone to tylosin by tyl G mutants of S. fradiae proves the absolute configuration of tylosin. Physicochemical data for tylactone and a unique component piece of tylactone are also reported.

A large series of C-23-modified derivatives of 5-O-mycaminosyltylonolide were synthesized, in which the C-23 hydroxyl group was replaced by halo, aryl ether or thioether, azido, amino or dialkylamino substituents via SN2 displacement reactions. The majority of derivatives possessed excellent in vitro activity against a variety of aerobic and anaerobic bacteria. While some of the compounds treated experimental infections in rodents by parenteral administration, none showed any significant efficacy or bioavailability after oral dosing. Novel rearrangement products were obtained from some of the reactions; these were identified as 13,23-cyclopropyl-12,22-exomethylene and 13,23-cyclopropyl-12-alkoxy derivatives.

16-Deethylindanomycin (A83094A) is a novel pyrrole-ether antibiotic produced by a strain of Streptomyces setonii. The antibiotic, which is structurally similar to indanomycin (X-14547A), is active in vitro against Gram-positive bacteria as well as coccidia.

The synthesis and antirhinovirus activity of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine (4 and 5) are reported. The structural assignments of 4 and 5 are based upon 13C NMR spectra of both isomers and also X-ray analysis of 5. The anti-isomer 5 was more potent than the syn-isomer 4 when compared as an inhibitor of rhinovirus multiplication in vitro. Both isomers inhibited multiplication of 15 different serotypes of rhinovirus.

A plasmid conferring resistance to the aminocyclitol antibiotic hygromycin B was isolated from Escherichia coli. The gene conferring resistance to this drug was cloned in pBR322, and the gene was localized to a fragment of ca. 1,510 base pairs. Resistance to hygromycin B is determined by an aminocyclitol phosphotransferase that modifies hygromycin B and structurally related antibiotics. The specific modification of hygromycin B is a phosphorylation of the hydroxyl on the 4 position of the cyclitol ring (hyosamine). The presence of the phosphotransferase in E. coli correlates with reduced accumulation of [14C]hygromycin B.

It is proposed, based upon comparisons with apomorphine, that the rigid pyrroleethylamine moiety of the ergolines is the portion of the molecule responsible for dopamine agonist activity. In support of this hypothesis, bicyclic and tricyclic ergoline partial structures 6, 11, 25, and 35 have been synthesized. In addition, some pyrazole isosters (37, 38, 40, and 45) of these rigid pyrroleethylamines have been made. All of the classes show dopaminergic activity in prolactin inhibition and in lesioned rat turning assays. The most potent drugs, the linear tricyclic pyrazoles 38 (R = Pr) and 40 (R = Pr), are comparable in potency with the highly active ergoline pergolide (41).

The synthesis and serotonin receptor subtype affinity of a series of ergolines are described. High selectivity for the 5-HT1 subtype was found with a number of 8-substituted (3 beta, 5 beta)-9,10-didehydro-6-methylergolines. The more potent and selective of these compounds increased the concentration of serotonin and decreased the concentration of 5-HIAA in rat brain and increased corticosterone concentration in rat serum. Oral administration of 13, (3 beta)-2,3-dihydrolysergine, produced long-lasting decreases in serotonin turnover. Compound 13 lacked substantial dopaminergic activity as measured by its effects on dopamine turnover in whole brain or striatum and its affinity for alpha-adrenergic binding sites was significantly less than for 5-HT1 binding sites. The increases in serum corticosterone concentrations produced by 13 were not blocked by the serotonin uptake inhibitor fluoxetine or by the serotonin synthesis inhibitor p-chlorophenylalanine, suggesting that 13 exerts its effects through direct stimulation of serotonin receptors.

We recently prepared a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated for their ability to displace [3H]CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists). Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced [3H]CPP binding with IC50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively. The rest of the compounds prepared were weakly active or inactive in these assays. The pattern of activity observed for this series parallels that observed for the acyclic series of omega-phosphono-alpha-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive. Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.