Leucine Enkephalin Analogues Containing a Conformationally Restrained N-Terminal Amino Acid Residue

Regiospecific and conformationally restrained analogs of melphalan and DL-2-NAM-7 have been synthesized and their affinities for the large neutral amino acid transporter (LAT1) of the blood–brain barrier have been determined to assess their potential for accessing the CNS via facilitated transport. Several analogs had Ki values in the range 2.1–8.5 μM with greater affinities than that of either L-phenylalanine (Ki = 11 μM) or melphalan (Ki = 55 μM), but lower than DL-2-NAM-7 (Ki = 0.08 μM). The results indicate that regiospecific positioning of the mustard moiety on the aromatic ring in these analogs is very important for optimal affinity for the large neutral amino acid transporter, and that conformational restriction of the DL-2-NAM-7 molecule in benzonorbornane and indane analogs leads to 25- to 60-fold loss, respectively, in affinity.

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“…The final mustard products, 5a – 5d , were further purified by preparative HPLC prior to biological evaluation. 18 …”

mentioning

confidence: 99%

“…Mustard 6 was obtained from 19 as described above for products 5a – 5d , and was purified by preparative HPLC prior to biological evaluation. 18 …”

mentioning

confidence: 99%

Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 and their affinities for the large neutral amino acid transporter (system LAT1) of the blood–brain barrier

Matharu

Oki

Worthen

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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“…The [b-(benzylthio)-b,b-cyclopentamethylenepropionic acid [75], 2-aminoindan-2-carboxylic acid (Aic) [49,54], Boc-Aic [53], D,L-2-aminotetralin-2-caboxylic acid (Atc) [45,49] and Boc-D,L-Atc [48] were synthesized in this laboratory using routine procedures. For both Aic and D,L-Atc the spirohydantoin version of the Strecker synthesis [51,52] was applied.…”

Section: Experimental Partmentioning

confidence: 99%

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

et al. 1997

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We report the solid-phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1-12) of the potent non-selective antagonist of the antidiuretic (V2-receptor), vasopressor (V1a-receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT-receptor) responses to oxytocin (OT), [1(-beta mercapto-beta,beta-pentamethylenepropionic acid)-2-O-ethyl-D-tyrosine 4-valine] arginine vasopressin [d(CH2)5D-Tyr(Et)2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3 (Tic3) analogue of (A). Peptides 1-12 have the following substituents at position three in (A): (1) Pro; (2) Oic; (3) Atc; (4) D-Atc; (6) D-Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr-NH2(9) analogue of (B): Peptide (14) is the D-Cys(6) analogue of (B). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V2 and V1a assays and in vitro (no Mg2+)n oxytocic assays. With the exception of the D-Phe3 peptide (No. 6), which exhibits very weak V2 agonism (approximately 0.0017 U/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro3, Oic3, Tyr3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr-NH2(9) and D-Cys(6) substitutions in (B) are also well tolerated. The anti-V2 pA2 values of peptides 1-5 and 7-14 are as follows (1) 7.77 +/- 0.03; (2) 7.41 +/- 0.05; (3) 6.86 +/- 0.02; (4) 5.66 +/- 0.09; (5) approximately 5.2; (7) 7.25 +/- 0.08; (8) 6.82 +/- 0.06; (9) 7.58 +/- 0.05; (10) 7.61 +/- 0.08; (11) 7.59 +/- 0.07; (12) 7.20 +/- 0.05; (13) 7.57 +/- 0.1; (14) 7.52 +/- 0.06. All analogues antagonize the vasopressor responses to AVP, with anti-V1a pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti-OT pA2 values ranging from 5.79 to 7.94. With an anti-V2 potency of 7.77 +/- 0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti-V2 pA2 = 7.81 +/- 0.07). These findings clearly indicate that position three in AVP V2/V1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe3 analogues of (A), together with the excellent retention of V2 antagonism by the Tyr-NH2(9) and D-Cys6 analogues of (B) are promising new leads to the design of potent and possibly orally active V2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH).

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Inhibitors of Phenylalanine Ammonia‐Lyase: 2‐Aminoindan‐2‐phosphonic Acid and Related Compounds

1992

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Key Words: 2-Aminoindan-2-phosphonic acid/Enzyme inhibition/Phenylalanine ammonia-lyase 2-Aminoindan-2-phosphonic acid (3) was synthesized for the first time both directly from 2-indanone (7) as well as by alkylation of ethyl diethoxyphosphorylacetate with 1,2-bis(bro-momethy1)benzene (9) via 10 -12, respectively. 2-Hydroxyindan-2-phosphonic acid (5) was obtained also from 7 via its diisopropyl ester 8. Compound 3 was found to be a potent

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Leucine Enkephalin Analogues Containing a Conformationally Restrained N-Terminal Amino Acid Residue

Cited by 9 publications

References 44 publications

Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 and their affinities for the large neutral amino acid transporter (system LAT1) of the blood–brain barrier

Regiospecific and conformationally restrained analogs of melphalan and dl-2-NAM-7 and their affinities for the large neutral amino acid transporter (system LAT1) of the blood–brain barrier

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

Inhibitors of Phenylalanine Ammonia‐Lyase: 2‐Aminoindan‐2‐phosphonic Acid and Related Compounds

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