Practical methodologies for the synthesis of indoles.

A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT1D agonists, benzodiazepine receptor ligands, 5-HT3 antagonists, dopamine D2 antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.

A genetic algorithm for flexible molecular overlay and pharmacophore elucidation.

Publisher Summary This chapter discusses the preparation of antigenic hapten-carrier conjugates. Substances of molecular weight less than 1000 are not ordinarily antigenic. However, antibodies can be raised to small molecules, by immunization, with conjugates made up of low molecular weight substances (haptens) covalently linked to proteins or synthetic polypeptides. The protein carriers used in various laboratories include: globulin fractions, the serum albumins of various species, hemocyanin, ovalbumin, thyroglobulin, and fibrinogen. Hapten-protein conjugates of serum albumin are, in general, more soluble than conjugates of γ-globulin or of ovalbumin. In this study, it is attempted to incorporate it into a general survey of the methods of preparing immunogenic haptenprotein conjugates, in which the hapten is a pharmacologically interesting compound. The arrangement is governed by the nature of the reactive functional groups of the hapten. In this way, the information can be applied most easily to new compounds being considered for use as determinant groups. Various procedures described are discussed, by specific examples, presenting practical aspects of the experimental methods.

[4] The preparation of antigenic Hapten-Carrier conjugates: A survey

Identification of the Binding Site for a Novel Class of CCR2b Chemokine Receptor Antagonists BINDING TO A COMMON CHEMOKINE RECEPTOR MOTIF WITHIN THE HELICAL BUNDLE

Synthetic approaches to 3-(2-nitroalkyl) indoles and their use to access tryptamines and related bioactive compounds.

Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

The Leimgruber-Batcho indole synthesis

C-glycosyl nucleosides. II. A facile synthesis of derivatives of 2,5-anhydro-D-allose.

A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.

Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.

* Foreword (Alexander T. Shulgin) * Preface * Acknowledgments * Chapter 1. The Botany of Anadenanthera * Taxonomic Background * Species Descriptions * Appendix: Synonyms and Indigenous Names * Chapter 2. Archaeological Evidence for Anadenanthera Preparations * The Taino * The Central Andes * The Northern Andes * Appendix: Archaeological Evidence for Anadenanthera Use * Chapter 3. Anadenanthera in Non-Andean South America * The Orinoco Basin * The Amazon Basin * The Southern Amazon Basin Periphery * Appendix: Indigenous Use of Anadenanthera in the Orinoco-Amazon Basin and Its Southern Periphery * Chapter 4. The Chemistry of the Genus Anadenanthera * Chemical Makeup and Commercial Uses of Anadenanthera * Biosynthesis of the Anadenanthera Alkaloids * Biochemical Systematics of Anadenanthera * Appendix: Species of Piptadenia from South America Studied for the Presence of Alkaloids * Chapter 5. The Pharmacology of Bufotenine * Whole Animal Research * Basic Pharmacology * Human Studies * Appendix: Chemical Structures of Anadenanthera-Based Drugs * Chapter 6. Summary and Conclusions * Bibliography * Index * Reference Notes Included

David B. Repke

Papers

2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

The Leimgruber-Batcho indole synthesis

C-glycosyl nucleosides. II. A facile synthesis of derivatives of 2,5-anhydro-D-allose.

Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.

Anadenanthera: Visionary Plant of Ancient South America