Antagonists of substance

Folkers, K., Horig, J., Rosell, S., BjOrkroth, U. Chemical design of antagonists of substance P, Acta Physiol. Scand. 1981, 111, 505-506. 

The cryptostylines and their analogues have been used as pharmacological probes, such as the Dj dopamine receptor, an antagonist of substance P, and a peptide neurotransmitter. Propose a catalytic asymmetric synthesis of (S) (+) cryptostyline II starting from methyl 2 (2 formyl 4,5 dimethoxyphenyl)acetate and 4 bromo 1,2 dimethoxybenzene. 

These are a family of peptides which include substance P, isolated in 1931 but only sequenced in 1971. This peptide has been extensively studied since it was the first major peptide to be extracted from brain but only now are useful antagonists becoming available. Two closely related peptides were then isolated from mammalian tissues and can be added to a number of other tachykinins, many of which are found in amphibians. The name tachykinins originated from the vasoactive effects of substance P but the nomenclature has been resolved into calling the three major mammalian peptides substance P, neurokinin A (NKA) and neurokinin B (NKB) with the corresponding receptors being numbered 1 to 3. The order of potencies at the three receptors as follows ... 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

Short-term toxicities of adjuvant chemotherapy are generally well tolerated, especially with the availability of serotonin-antagonist and substance P/neurokinin 1-antagonist antiemetics and colony-stimulating factors. 

Naltrexone (ReVia). Naltrexone is a very potent antagonist of the actions of opiates. It has been used to reduce the rewarding effects of not only opiates but alcohol as well. Like buprenorphine, naltrexone appears to reduce craving for opiates by blocking their pleasurable effects. Naltrexone is not useful for detoxification and in fact worsens withdrawal. Naltrexone can be useful for maintenance treatment in those patients motivated to achieve total abstinence. It is taken at a constant dose of 50mg/day. A sustained-release depot formulation currently under development will likely help to overcome adherence issues that often undermine treatment for substance use disorders. 

The generic name of the cacao tree (Theobroma) means food of the Gods and gives its name to a caffeine-like stimulant, theobromine (a methylxanthine). It has been claimed that the theobromine in chocolate is responsible for its addictive characteristics. This is based on the fact that methylxanthines bind to adenosine receptors in the central nervous system and act as antagonists to this neurotransmitter (Chapter 14). However, another group of substances, the amides formed between ethanolamine and unsaturated fatty acids, are also possible candidates for the title of the chocolate drug . 

Substances that bind Ca "" ions (e. g., citrate) prevent Gla-containing factors from attaching to the membrane and therefore inhibit coagulation. Antagonists of vitamin K, which is needed for synthesis of the Gla residues (see p. 364) also have anticoagulatory effects. These include dicumarol, for example. 

Pharmacology Aprepitant is a selective high-affinity antagonist of human substance... 

Ono H, Mishima A, Ono S, Fukuda H, Vasko MR (1991) Inhibitory effects of donidine and tizanidine on release of substance P from slices of rat spinal cord and antagonism by a-adrenergic receptor antagonists. Neuropharmacology 30, 585-589... 

All the protein-based potential therapeutics discussed above fail to meet any of these criteria. Low molecular mass antagonists of IL-5 or its receptor may prove of most use. A number of research teams are screening for such substances. The development strategies pursued include ... 

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