Tachykinin receptor antagonists

A non-peptide NK3 receptor antagonist (SB235375), with low penetrance into the central nervous system, inhibited citric acid induced cough and airways hyperreactivity in the guinea pig (Hay et al. 2002 Daoui et al. 1998) but its development has been suspended. 

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Tachykinins and their Receptors. Table 6 Examples of selective and non-selective tachykinin receptor antagonists... 

It should be mentioned here that discovery of the tachykinin receptor antagonists has not been limited to the NKi receptor, as non-peptide antagonists for the NK2 receptor (e.g SR48.968) and NK3 receptor (e.g. SR142.801) are known. 

Furthermore, the discovery of novel compounds with higher therapeutic potential can be foreseen. A selection of compounds which were filed recently for the treatment of pain and migraine is given below. As all of the nonpeptide tachykinin receptor antagonists arose from... 

Durette, P., Kopka, I., MacCoss, M., Mills, S., (Merck Co.) Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists, EP 5929094 (1999). 

Maggi, C. A., Patacchini, R., Rovero, P., Giachetti, A. Tachykinin receptors and tachykinin receptor antagonists, J. Auton. Pharmacol. 1993, 13, 23-93. 

Walpole, C., Ko, S. Y., Brown, M., Beattie, D., Campbell, E., Dickenson, F., Ewan, S., Hughes, G. A., Lemaire, M., Lerpiniere, J., Patel, S., Urban, L. 2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models, J. Med. Chem. 1998b, 41, 3159-3173. 

Utility Tachykinin Receptor Antagonistics for Treating Respiratory Tract... 

Solway, J., Kao, B.M., Jordan, J.E. etal. (1993). Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea-pigs. J. Clin. Invest. 92, 315-323. 

Sarau HM, Griswold DE, Potts W, et al. Nonpeptide tachykinin receptor antagonists I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. / Pharmacol Exp Ther. 1997, 281(3) 1303-1311. 

New initiatives in developing migraine treatments include the use of TACHYKININ RECEPTOR ANTAGONISTS and CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS. 

CP 96345 is a substituted quinuclidine, a substituted isoindole, a TACHYKININ RECEPTOR ANTAGONIST selective for the NK,-receptor subtype. It also has ion channel-blocking properties, and is used as a pharmacological tool. 

It may also have ANTIPSYCHOTIC activity, dapiprazole hydrochloride dapiprazole. dapitant [inn] (RPR 100893) is a substituted isoindole, a TACHYKININ RECEPTOR ANTAGONIST, selective for the NK,-receptor subtype. It has potential as an ANTIMIGRAINE AGENT, dapsone [ban, inn, usan] is a sulphone with actions similar to SULPHONAMIDES and with ANTIBACTERIAL activity. It can be used as an antileprotic and for infective dermatitis herpetiformis. and is being investigated for the treatment and prevention of Pneumocystis carinii pneumonia (e.g. in AIDS), daptomycin [ban, inn, usan] is an (aminoglycoside) antibiotic. It has antibacterial properties. 

OSalmid [inn, jan] (L171 8 and many other names) is a benzamide and has been used as a CHOLERETIC AGENT, osanetant [inn] (SR 142801) is a substituted piperidinyl-methylacetamide. a TACHYKININ RECEPTOR ANTAGONIST selective for the NKs-receptor subtype. 

These observations on sensory nerve endings can probably be extended mechanistically and transposed to other sites (e.g. the airways). In skin it seems certain that a local axon reflex is involved in the triple response described by Lewis, whereby there is flush, flare and wheal manifestation of which denotes neurogenic inflammation. Many of these manifestations can be blocked with bradykinin and tachykinin receptor antagonists, and antihistamines, used in concert. It is now presumed that these basic observations in the skin can be applied to conjunctivae and the airways, and there is every reason to suppose that much the same events are involved in (defensive) reaction to exogenous irritant chemicals. 

Howson, W. (1995) Rational design of tachykinin receptor antagonists. Drug New el Perspectives 8. 97-103. 

Advenier C, EmondsAlt X (1996) Tachykinin receptor antagonists and cough. Pulm Pharmacol... 

Moreaux B, Nemmar A, Vincke G, Halloy D, Beerens D, Advenier C, Gustin P (2000) Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs. Eur J Pharmacol 408 305-312... 

Yasumitsu R, Hirayama Y, Imai T, Miyayasu K, Hiroi J (1996) Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs. Eur J Pharmacol 300 215-219... 

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