ABSTRACT
The structures of neoefrapeptins A to N, peptides with insecticidal activity, were elucidated. They showed a close similarity to efrapeptin. However, all neoefrapeptins contained the very rare amino acid 1-amino-cyclopropane-carboxylic acid and some of them also contained (2S,3S)-3-methylproline. The neoefrapeptins are the first case, in which these amino acids are found as building blocks for linear peptides. They were identified by comparison of the silylated hydrolyzate to reference material by GC/MS (EI-mode). The sequence was elucidated using mass spectrometry (ESI+ mode). Full scan spectra showed two fragments in high yield, even under mild ionization conditions. MS/MS spectra of these two fragments yielded fragment rich spectra from which the sequence of the compounds was determined almost completely. The proteolytic cleavage with the proteinase papain yielded products that allowed to prove the rest of the sequence and the identity of the C-terminus to efrapeptin. The proteolytic cleavage products allowed furthermore to determine the position of the isobaric amino acids, pipecolic acid and 3-methylproline in neoefrapeptin F, as well as the location of R-isovaline and S-isovaline. Papain digestion was such established as a tool for structure elucidation of peptides rich in alpha,alpha-dialkylated amino acids. CD spectra suggested a 3(10) helical structure for neoefrapeptins A and F.
Subject(s)
Fungal Proteins/chemistry , Geotrichum/chemistry , Insecticides/chemistry , Peptides/chemistry , Alphaprodine/analogs & derivatives , Alphaprodine/analysis , Amino Acid Sequence , Amino Acids, Cyclic/analysis , Circular Dichroism , Gas Chromatography-Mass Spectrometry , Molecular Sequence Data , Molecular Structure , Papain/chemistry , Pipecolic Acids/analysis , Spectrometry, Mass, Electrospray IonizationABSTRACT
A number of racemic 1,3-dimethyl-4-phenylpiperidines which serve as intermediates in the synthesis of opioid analgesics have been resolved on two commercially available high-performance liquid chromatography columns containing cellulose-based chiral stationary phases: Chiralcel OD and Chiralcel OJ. The resolution results were complementary between the two columns. Also, the polarity of substituents appears to play an important role on the ability of the Chiralcel OD column to resolve pairs of enantiomers.
Subject(s)
Alphaprodine/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Alphaprodine/analysis , Spectrophotometry, Ultraviolet , StereoisomerismABSTRACT
The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17). In the mouse writhing test the spiropethidine 2 is not analgesic active up to a dose of 20 mg/kg body weight (bw). In the spirocyclic prodine series the methylated lactone 4c is the most active analgesic with an ED50-value (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.
Subject(s)
Alphaprodine/analogs & derivatives , Analgesics/chemical synthesis , Meperidine/analogs & derivatives , Alphaprodine/chemical synthesis , Alphaprodine/pharmacology , Analgesics/pharmacology , Animals , Meperidine/chemical synthesis , Meperidine/pharmacology , Mice , Pain Measurement/drug effectsABSTRACT
The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.
Subject(s)
Alphaprodine/analogs & derivatives , Analgesics/chemical synthesis , Antipsychotic Agents/chemical synthesis , Receptors, Dopamine/drug effects , Receptors, Opioid/drug effects , Alphaprodine/chemical synthesis , Alphaprodine/chemistry , Alphaprodine/pharmacology , Analgesia , Animals , Apomorphine/pharmacology , Binding, Competitive , Brain/metabolism , Dihydromorphine/metabolism , Indicators and Reagents , Isomerism , Male , Mice , Molecular Structure , Rats , Rats, Inbred Strains , Receptors, Dopamine/metabolism , Receptors, Dopamine D2 , Receptors, Opioid/metabolism , Receptors, Opioid, mu , Spiperone/pharmacology , Stereotyped Behavior/drug effects , Structure-Activity RelationshipABSTRACT
Some 4-phenyl-4-piperidinols, corresponding esters, and related compounds with a p-fluorobutyrophenone chain on nitrogen were synthesized and evaluated in in vitro and in vivo tests in order to examine their ability to interact contemporaneously with opioid and dopamine receptors. The propionyloxy derivatives showed a good combination of analgesic and neuroleptic activity. With a 3-methyl substituent on the piperidine ring, the beta-configuration was the more active form not only for analgesic activity, as expected from previous results on prodines, but also for neuroleptic activity. Haloperidol and its propionate were also tested as reference compounds.
Subject(s)
Alphaprodine/pharmacology , Analgesics/chemical synthesis , Antipsychotic Agents/chemical synthesis , Butyrophenones/pharmacology , Adenylyl Cyclase Inhibitors , Alphaprodine/analogs & derivatives , Animals , Apomorphine/pharmacology , Dihydromorphine/metabolism , Mice , Spiperone/metabolism , Stereotyped Behavior/drug effectsABSTRACT
The preparation and resolution of 1,3,3-trimethyl-4-phenyl-4-(propionyloxy)piperidine (5,3-methylprodine) are described, and the results of the antinociceptive activities of the products by hot-plate (mice) and tail-withdrawal (rats) tests are shown to support proposals made from a recent analysis of the stereochemical structure-activity relationships of C-methyl derivatives of the reversed ester of meperidine. Data of absolute configuration were obtained by X-ray crystallography of a hydrobromide salt.
Subject(s)
Alphaprodine/analogs & derivatives , Analgesia , Alphaprodine/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Mice , Molecular Conformation , Rats , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
Analogs of the prodine analgesics were prepared and tested for analgesic activity. A good correlation seems to exist between the energy level of the highest occupied molecular orbital and biological activity. The energy level of the highest occupied molecular orbital of the aryl moiety of these analogs may permit a charge transfer interaction between the aryl groups of the analgesic molecules and their receptors with the aryl groups acting as charge donors.
Subject(s)
Alphaprodine/analogs & derivatives , Receptors, Drug/metabolism , Alphaprodine/metabolism , Alphaprodine/pharmacology , Analgesics , Animals , Chemical Phenomena , Chemistry, Physical , Electrochemistry , Mice , Reaction Time/drug effectsABSTRACT
The receptor binding affinities of some diastereoisomeric prodine analgoues have been compared with their analgetic activities determined by the hot-plate test in mice. The close correlation found between these potencies indicates that the relative analgetic activities of the alpha/beta isomers are determined primarily by the appropriate association to the receptor sites.
Subject(s)
Alphaprodine/analogs & derivatives , Analgesics, Opioid , Receptors, Opioid/metabolism , Alphaprodine/metabolism , Alphaprodine/pharmacology , Animals , Brain/metabolism , In Vitro Techniques , Isomerism , Molecular Conformation , Rats , Reaction Time/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and analgetic activity of analogues of prodine-type analgetics in which the conformation of the piperidine ring is restricted in the boat form using the 2-azabicyclo (2.2.2)octane nucleus are reported. One of these analogues, 2-methyl-6-trans-phenyl-6-cis-propionoxy-2-azabicyclo (2.2.2)octane (3), showed significant analgetic activity (ED50 equals 3.1 mg/kg).
Subject(s)
Alphaprodine/analogs & derivatives , Analgesics/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Alphaprodine/chemical synthesis , Alphaprodine/pharmacology , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Isomerism , Male , Molecular Conformation , Pain , Rats , Reaction Time/drug effects , Structure-Activity RelationshipABSTRACT
X-Ray crystallographic studies have been performed on the two diasteromeric racemates of 3-allyl-1-methyl-4-propionoxypiperidine hydrochloride (allylprodine hydrochloride) in an effort to determine the role of conformation in their interaction with analgetic receptors sites. The chiral orientation of the phenyl group in the highly potent isomer, (+)-1, is qualitatively in conformity with the stereo structure-activity relationship found among other analgetic 4-phenylpiperdines. The fact that (+)-2, a relatively weak analgetic with no stereoselectivity, also possesses this feature indicates that this conformational arrangement per se does not ensure high potency. The data suggest that the very potency and stereoselectivity which the allylic double bond confers to (+)-1 are due primarily to the interaction of this bond with an accessory site on the receptor.
