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INTERNAL ACTIVITY OF BIOLOGICALLY ACTIVE COMPOUNDS. LIGAND-RECEPTOR RECOGNITION

Explore the principles of ligand-receptor recognition and the internal activity of biologically active compounds, including receptors types and their localization in the brain. Discover how benzodiazepine receptor ligands and GABA influence receptor recognition.

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INTERNAL ACTIVITY OF BIOLOGICALLY ACTIVE COMPOUNDS. LIGAND-RECEPTOR RECOGNITION

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  1. INTERNAL ACTIVITY OF BIOLOGICALLY ACTIVE COMPOUNDS. LIGAND-RECEPTOR RECOGNITION A.V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine

  2. FisherEmilGerman (1852—1919) German organic chemist Chemistry of natural compounds, peptides, purines, carbohydrates Nobel Prize in Chemistry (1902) Erlich Paul (1854—1915) Germanchemotherapistandbacteriologist. Founder ofmodernchemotherapy (Salvarsan). Theory of receptors. Nobel Prize in Physiology and Medicine (1908)

  3. DEFINITIONS The term receptor formally is defined as a cellular macromolecule that is concerne with chemical signalling between or within cells. The term recognition site(s) refers to the fragment(s) on the receptor macromolecule to which agonist bind.

  4. Functional binding sites on the GABAA receptor Richards G, Schoch P, Haefely W: Benzodiazepine receptors: new vistas. Seminars in Neuroscience 1991, 3:191–203.

  5. RECEPTORS TYPES Principles of the agonist action on processes controlled by receptors I – direct influence on the ion channels penetrability (N-cholinoreceptors, GABAA – receptors) II – indirect influence (through the G-proteins) on the ion channels penetrability or on the activity of enzymes regulating formation of secondary transmitters (M-cholinoreceptors, adrenoreceptors) III – direct influence on activity of effector enzyme of tirosinkinase (insulin receptors, receptors of series of growth factors) IV – influence on the transcription of DNA (steroidal hormones, tireoidal hormones)

  6. GABA – RECEPTORS

  7. Targetsforanxiolytics anticonvulsants miorelaxants hypno-sedative agents, etc. pharmacologically and clinically significant preparations. BDR - allosteric modulatory sites onGABAАR. MULTIPLICITY ofGABAАR  - subunits, are labeled by3Н-flunitrazepam  - subunits, are labeled by3Н-muscimol  - subunits, are clonedusingm-RNA Averagemolecularmasses of - and-subunits are close (within 50-57 кD) Differentsubunitsare codedby differentDNA GABAАR

  8. LOCALISATION OFGABAАSUBTYPESINMAMMALIAN BRAIN

  9. Ligands of CBDR Midazolam (full agonist) Bretazenil (partial agonist) Flumazenil (antagonist) Ro15-4513 (partial inverse agonist) Ro 19-4603 (inverse agonist)

  10. Ligands of CBDR – derivatives ofdifferentheterocyclicsystems Diazepam Benzodiazepines -Carbolines Cyclopirrolones Abecarnil Zopiclon

  11. Ligands of CBDR – derivatives ofdifferentheterocyclicsystems Imidazopiridines Imidazopirimidines Piridones Zolpidem Divaplon Ro 41-3696

  12. - BD - GABA - Cl - Scheme of GABAА receptor R + L ↔ RL, biological response (1)2(2)22 GABAАR: supramolecular heteropentameric assembly which forms (Cl-, HCO3-) anionic channel. Includes -,-,-,-,-types of subunits. -,- and-types have several isoforms. General number of variants of subunits– about 20.

  13. TWO-STATE MODEL Two-state model to explain the bidirectional modulatory effects of benzodiazepine (BZR) receptor ligands on GABAA receptor channel function. Fragments of two subunits with their interphase are shown. The two inerconvertible states, one with a positive allosteric influence, the other with negative allostericinfluence, oscillate with the rate constants  and . BZR agonists are shown to fit the positive modulatory state. BZR inverse agonists fit into the negative modulatory state. Antagonists bind equally well to both states. The bottom diagram indicates that GABA binding to its site (GA-R) shifts the BZR into the positive modulatory state, increasing the binding of agonists and decreasing that of inverse agonists without affecting that of pure antagonists (so-called GABA shift) (W.E. Haefely, The Challenge of Neuropharmacology, 1994, 15)

  14. INTERNAL ACTIVITY Internal activity (IА) – it is ligand ability to provoke receptor conformation changes, leading to signal transformation into physiological response. Full agonists: high positive IA Inverse agonists: high negative IA Antagonists: IA = 0

  15. INFLUENCE OF GABA ON THE RECOGNITION OF BDR RECEPTORS

  16. INTERNAL ACTIVITY OF BENZODIAZEPINE RECEPTOR LIGANDS Convulsants  Anxiogenes   Anticonvulsants  Sedation Anxiolytics

  17. Effect of the concentration of acetycholine (neurotransmitter) on muscle contvaction. Dose-response curves are a means of measuring drug-receptor interactions and are standart method comparing the potencies of compounds that interact with particular recepor. Muscle Contraction, % Kd -lgCACh (M)

  18. Dose – response curve for an agonist Agonist produce the same maximal response as the neurotransmitter. Muscle Contraction, % -lgCagm (M)

  19. Dose – response curve for an antagonist compound shows no response. Muscle Contraction, % -lgCcomp. (M)

  20. Influence of competitive antagonist on the response of the neurotransmitter Muscle Contraction • Without competitive antagonist (Com. Ant) • With Com.Ant • With 2 doses Com. Ant • With 3 doses Com.Ant 1 2 4 3 If antagonist is added to the neurotransmitter (acetylcholine) effect of the neurotransmitter is blocked until a higher concentration of the neurotransmitter is added. Degree of antagonist is dependent on the relative concentrations of the agonist and antagonist of the same receptor.

  21. Influence of noncompetitive antagonist on the response of the neurotransmitter 1 • Without Non Com. Ant • + Non Com. Ant • + 2 doses Non Com. Ant • + 4 doses Non Com. Ant Muscle Contraction, % 2 3 4 -lgCAiCh (M) Degree of blocking of a noncompetitive antagonist of the amount of agonist present. On this case two different binding sites may be involved.

  22. Dose – response curve for a partial agonist Muscle Contraction, % 45% -lgCp.aq On a case of partial agonist some response is elicited, but not a full response, regardless of how high the concentration of ligand used.

  23. The values Ki and GABA-shift of cinazepam 3-hydroxyphenazepam and zopiclon

  24. Functionalactivity ethyl--carboline-3-carboxilate (β-CCE) (4) 3,3′-Bis-[7-bromo-5-(o-chloro)phenyl-1,3-dihydro-2Н-1,4-benzodiazepine-2-one]amine (3) 3-hydroxyphenazepam (2) phenazepam (1) Partial inverse agonist S.Yu. Makan, К.S. Andronati, ….2005

  25. RELATIONSHIP BETWEEN ANTICONVULSIVE ACTIVITY OF BD AND THEIR AFFINITY FOR BDR Log(1/ED50)=-0,78log(Ki)+1,41; R=0,95

  26. Relationship betweenlipophilicityof dihydro-1,4-benzodiazepine-2-ones andtheir affinityforBDR

  27. Scheme of inclusive complex“pharmacophore - BDR” S2 S3 L2 H2 S1 H1 H1 andH2 – Н-bonds ofdonorsitesonreceptor protein L1 andL2 – lipophilicfragmentsof ligand S1 andS2 – regionsof stericrepulsioninligand-bindingdomain ofreceptor Q. Huang et al. Drug Design and Discovery, 1999, 16, 55

  28. Structure-activity relationshipof dihydro-1,4-benzodiazepine-2-ones R1 –groups> СН3 are not favorable forincrease of the activity >C=O –play important role: interactwithcationicsite of the receptor R2 – groups> СН3 – are not favorable =N –interactwithcationicsite of the receptor R3 –electronoacceptorandhydrofobicgroupspromoteincrease of the activity R4 –substituentsare not favorable R5 –cooperative areelectronoacceptor, hydrophylicgroups R6 –substituentsinpositions 8 and 9 are not desirable

  29. 5-HT RECEPTORS CHARACTERISTICS

  30. TRANSMEMBRANE TOPOLOGY OF 5-HT1A R

  31. LIGANDS OF 5-HT1A RECEPTORS

  32. AFFINITY TO 5-HT1A AND D2 RATS HEAD BRAINS RECEPTORS AND ANXIOLYTIC ACTIVITY OF N-(ARYLPIPERAZINYLALKYL)PHTALIMIDES S.A. Andronaty, S.G. Soboleva, S.Yu. Makan Chem.-Pharm. Zhurn. – 2003. – Vol. 37. – N. 1, – P. 17-21

  33. THE ANXIOLYTIC ACTIVITY OF N-(ARYLPIPERAZINYLALKYL)PHTHALIMIDES AND THEIR AFFINITY FOR 5-HT1A- AND FOR D1-RECEPTORS S.A. Andronaty, T.A. Voronina, V.M. Sava, G.M. Molodavkin, S.Yu. Makan, S.G. Soboleva. Molecular Recognition and Inclusion. – Ed. A.W. Coleman. – Kluwer Academic Publishers, Netherlands, 1998. – P. 245 – 249.

  34. THREE-POINT MODEL OF THE PHARMACOPHORE FOR BINDING BUSPIRONE ANALOGS AT 5-HT1A R Z.Chilmonczyk,… Arch.Pharm.Med.Chem., 1997, 330, 146

  35. PHENYLPIPERAZINYLBUTYLBARBITURIC ACIDS Maximum affinity for 5HT1A R (Ki =1.26 nM) and anxiolytic activity (107 8.1 number of punished water intakes) Anticonvulsant activity (pentamethylentrazol) ED50 = 135 (122,5 – 142.0)mg/kg Hypnotic activity (ED 99 = 80 mg/kg) S. Andronati, S. Makan …, Chem. Pharm. J., 2002 T. Karaseva…, Voprosi Biolog. i Med. Chem., 2005

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