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About one hundred alkaloids are known from the family Amaryllidaceae. In their route of biosynthesis they bear several resemblances to the morphine alkaloids. In each type there are two six-membered rings derived from aromatic amino acids; and the additional ring closures are apparently produced by a mechanism of phenolate free radical coupling. The carbon-nitrogen skeletons of the presumed precursors in the two groups differ from each other by one carbon atom

Buprenorphine demonstrates a well developed and reproducible biphasic dose-response curve in the rat radiant heat tail flick assay. Prior administration of naloxone produces a shift of the total curve to the right and a result of this behaviour is that over a limited dose range, the antagonist potentiates rather than decreases the response due to buprenorphine. Measurement of buprenorphine brain levels failed to demonstrate saturation of receptors over the dose range producing the biphasic response though saturation effects were observed at higher doses. It is suggested that these data support the existence, in the whole animal, of two functionally related opiate receptor populations.

The diverse group of natural products classed as terpenoids and steroids includes some compounds that contain nitrogen and are called alkaloids on that account. Biosynthetically they can be set apart from all other alkaloids because their carbon skeletons are derived from mevalonic acid, while most other alkaloids have their skeletons constructed largely of amino acid residues. This origin from a non-nitrogenous precursor raises a question as to the source of the nitrogen and the stage at which it enters the molecule. For the most part knowledge about the biosynthesis of these alkaloids is limited to the knowledge that they are indeed derived from mevalonic acid. In other cases even that conclusion is only an inference based on examination of structure. Certain alkaloids, otherwise non-terpenoid, that contain a terpenoid unit are also known and are treated in Chapter 10. Structures of some terpenoid alkaloids are given in Fig. 13-1.

A number of naturally occurring nitrogen compounds have basic properties in common with the alkaloids but are usually not classified as alkaloids because their structures are relatively simple. Their nitrogen atoms are not incorporated into heterocyclic skeletons; and they are seen to be derivable from amino acids by a few, simple reactions. Mere decarboxylation of amino acids produces simple amines which are never classed as alkaloids. Further modification of such simple amines by the introduction of methyl groups or hydroxyl groups or both gives rise to a group of ambiguously classified compounds that are sometimes called alkaloids. However, it seems useful to distinguish them by the name “protoalkaloids,” suggesting both their simple structures and their possible role as precursors of more typical alkaloids (cf. Chap. 1).

Although there appear to be no exceptions to the rule that proteins are composed solely of the L-isomers of amino acids, D-amino acids and derivatives of them do occur rather widely in living organisms. In some cases they have well-understood functions, but in other cases their occurrence raises interesting questions. Several peptide antibiotics contain D-amino acids (1). The peptido-glycans of Gram-positive bacterial cell walls contain D-glutamic acid, D-alanine, and D-asparagine (2). D-amino acids are also found in animals, chiefly annelids and insects (3). In this paper some aspects of D-amino acids in higher plants will be reviewed.

Ultimately, gross effects of alkaloids and other foreign molecules on the behavior of organisms must have their explanations in terms of specific molecular interactions and chemical reactions. In the course of its development, pharmacology has come from observations of total behavior to observations of gross physiological processes, observations on isolated organs and tissues, and elegant and detailed observations at the cellular level. In a few cases it has started to approach observations at the molecular level. Essential aspects of pharmacology have doubtlessly been overlooked in this chapter, and it should probably be regarded as a smattering of things that have been of interest to one biochemist rather than a balanced review. Where references to literature are not given, the reader is referred to the general sources [51,95,140,165,202,210,270]. Although most of the information in this chapter is from the pharmacological literature—i.e., dealing with animals—there are a few interesting reports dealing with biochemical effects of alkaloids on plants and bacteria. These are introduced at appropriate places rather than having a section to themselves.

While knowledge about the metabolism of alkaloids in the plants that synthesize them has only recently begun to be developed, pathways of alkaloid degradation by other organisms have been studied for many years, and in a few cases considerable detail is available. The special interest in this area arises, of course, from pharmacological effects of alkaloids, and therefore most studies relate to mammalian metabolism and to alkaloids of widespread use. It is frequently suggested that administered drugs are metabolically converted to the real physiologically active compounds. The metabolism of drugs is a subject of frequent review articles [28,76,134]; and since many drugs are either natural alkaloids or structurally related compounds, these reviews often include information pertinent to the present discussion. There are also two books dealing with the mammalian metabolism of foreign compounds in general [58,116]. Where not specifically annotated, information in this chapter has been derived from these five reviews. The metabolism of alkaloids by microorganisms has received less attention than their mammalian metabolism, but there is practical reason for such studies, since products of microbial transformation of alkaloids may in some cases themselves be pharmacologically valuable or serve as intermediates for chemical syntheses. There is one review in this area [68].

In spite of the large numbers and great diversity of alkaloid structures, it seems possible now to discern a few general principles that apply to the biosynthesis of many different alkaloids. Some broad theories of alkaloid formation have borne the test of many experimental investigations, some have received no support, some have been refuted, and some newcomers have not yet been tested adequately.

Several alkaloids are postulated to be derived from anthranilic acid. These include some rather simple substituted anthranilic acids, quinolines, and some with condensed ring systems of various types. Some of the parent nuclei of these alkaloids are as follows

Pyrrolizidine alkaloids are based on diols called necines which are esterified at one or both hydroxyl groups with a number of different acids, mostly dicarboxylic acids known as necic acids. Some examples of necines and necic acids are shown in Fig. 12-1. Structural variation among the necines is slight. Only about a dozen are known, and they differ from one another mostly in stereochemistry or degree of hydrogenation. Most of the necic acids have 10 carbon atoms arranged as follows: The acids of Crotolaria spp. differ in having only 6 or 8 carbon atoms, and a few other exceptions are known [1].

High-speed liquid chromatography can provide successful separations of two cinchona alkaloids, four opium alkaloids, or heroin-related narcotics. Poly G-300 is used as the liquid stationary phase. Both mechanical-coating and dynamic-coating techniques are employed; dynamic-coating techniques appear to be advantageous for some cases. With the latter technique the degree of partition and adsorption separation mechanisms can be controlled to facilitate separations which might be difficult otherwise. Quantitative analysis of three rapidly eluting opium alkaloids, at nanogram to microgram levels, is described; reasonable accuracy (± 10% or better) was obtained.

RICININE, the alkaloid of castor bean plants, is of interest since it is one of the very few natural products containing a nitrile group and since, as Leete and Leitz1 have shown, it is biogenetically derived from the vitamin, nicotinic acid. In our studies on the distribution and biogenesis of ricinine we have sought a semi-quantitative analytical method that would permit routine determination of ricinine in a large number of samples of plant tissue without tedious extraction and isolation procedures. Such a goal is hindered since ricinine is neutral and does not react with the usual ‘alkaloidal reagents’.

While knowledge about the metabolism of alkaloids in the plants that synthesize them has only recently begun to be developed, pathways of alkaloid degradation by other organisms have been studied for many years, and in a few cases considerable detail is available. The special interest in this area arises, of course, from pharmacological effects of alkaloids, and therefore most studies relate to mammalian metabolism and to alkaloids of widespread use. It is frequently suggested that administered drugs are metabolically converted to the real physiologically active compounds. The metabolism of drugs is a subject of frequent review articles [1–3]; and since many drugs are either natural alkaloids or structurally related compounds, these reviews often include information pertinent to the present discussion. Where not specifically annotated, information in this chapter has been derived from Refs. [1] and [2]. The metabolism of alkaloids by microorganisms has received less attention than their mammalian metabolism, but there is practical reason for such studies, since products of microbial transformation of alkaloids may in some cases themselves be pharmacologically valuable or serve as intermediates for chemical syntheses.

The above quotation may appear preposterously inappropriate in view of the vast literature on pharmacological effects of alkaloids. However, there is indeed little to relate regarding the biochemistry of these effects. Ultimately, gross effects of alkaloids and other foreign molecules on the behavior of animals must have their explanations in terms of specific molecular interactions and chemical reactions. In the course of its development pharmacology has come from observations of total behavior to observations of gross physiological processes, observations on isolated organs and tissues, and elegant and detailed observations at the cellular level. In very few cases has it started to approach observations at the molecular level. At the present, though, it seems important to suggest some of the problems and difficulties that necessarily attend any such molecular approach and to point to a few areas that seem to show some glimmers of success. Essential aspects of pharmacology are doubtless overlooked in this chapter, and it should probably be regarded as a smattering of things that have been of interest to one biochemist rather than a balanced review. Where references to literature are not given, the reader is referred to the general sources [1–7].

The infra-red spectroscopy of aqueous solutions has been hampered not only by the infra-red absorption of water itself, but also by the difficulty of finding material for absorption cell windows which would be insoluble in water and still sufficiently transparent in the desired region. This problem is particularly irksome to biochemists who are primarily interested in aqueous solutions. Several groups of workers1–4 have been successful in observing infra-red spectra in water solution by using cells sufficiently thin for absorption by water not to be excessive and by choosing materials such as silver chloride, barium fluoride, thallium bromide, etc., for windows. The expense and inconvenience of these special windows has prevented many from benefiting by this powerful technique, so that we have been led to consider the possibility of using polyethylene as a window material for aqueous solutions.