Bioorganometallic Chemistry of Ferrocene

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

https://pharmrev.aspetjournals.org/content/pharmrev/57/1/27.full.pdf

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Nervous connections between the trigeminal ganglia and cerebral blood vessels have recently been identified in experimental animals and have been termed the trigeminovascular system. Existence of this system in humans is inferential. Trigeminovascular neurons and their peripheral unmyelinated nerve fibers contain the neurotransmitter peptide substance P. Most newly synthesized substance P is transported from ganglion cell bodies to afferent nerve fibers, where depolarization-induced release of neurotransmitter into the wall of the cerebral blood vessel occurs. Substance P dilates pial arteries, increases vascular permeability, and activates cells that participate in the inflammatory response. The relationship of trigeminovascular fibers to the pathogenesis of vascular head pain sheds light on possible mechanisms of migraine and other central nervous system conditions associated with headache and inflammation.

The neurobiology of vascular head pain.

Neuroendocrine pharmacology of stress

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

Calcitonin Gene-Related Peptide: Physiology and Pathophysiology

Autoradiographic distribution of [3H]neurotensin receptors in rat brain: visualization by tritium-sensitive film.

Characterization and visualization of cholecystokinin receptors in rat brain using [3H]pentagastrin.

The vasoconstrictor effect of neuropeptide Y and related peptides in the guinea pig isolated heart

Differential neurobehavioral effects of neurotensin and structural analogues.

1 The stimulatory effects of neurotensin (NT) and several NT fragments were evaluated in two pharmacological preparations: rat stomach strips and isolated spontaneously beating atria of guinea-pigs.

2 In rat stomach strips, NT elicited a dose-dependent contractile effect in concentrations varying between 1.3 × 10-9 and 5.4 × 10-7 M.

3 The contractile effect of NT (1.3 and 5.4 × 10-8 M) in this tissue was not modified by atropine (3.4 × 10-7 M), methysergide (2.0 × 10-6 M), a mixture of cimetidine (8.0 × 10-6 M) and diphenhydramine (7.8 × 10-6 M), indomethacin (1.4 × 10-5 M), 8-Leu-angiotensin II (1.0 × 10-6 M), glucagon (2.0 × 10-6 M) or somatostatin (3.0 × 10-7 M).

4 Rat stomach strips desensitized by bradykinin (6.1 × 10-6 M) or substance P (7.4 × 10-6 M) maintained their sensitivities to NT (1.3 and 5.4 × 10-8 M).

5 In guinea-pig atria, NT produced a dose-dependent positive inotropic action in concentrations varying between 5.4 × 10-10 and 2.7 × 10-7 M.

6 The inotropic effect of NT (2.7 × 10-9 M) was not influenced by methysergide (2.8 × 10-6 M), atropine (3.4 × 10-7 M), practolol (1.5 × 10-5 M), 8-Leu-angiotensin II (1.0 × 10-6 M), or indomethacin (1.4 × 10-5 M), but it was reduced by 37% by cimetidine (4.0 × 10-5 and 2.0 × 10-4 M). A combination of cimetidine (4.0 × 10-5 M) and diphenhydramine (3.9 × 10-6 M) did not produce a greater inhibition of NT than cimetidine alone.

7 Atria desensitized by bradykinin (6.1 × 10-6 M) or glucagon (2.0 × 10-6 M) maintained their sensitivities to NT (2.7 × 10-9 M). Substance P was inactive both as an agonist or antagonist of NT.

8 These results suggest the existence of specific NT receptors in rat stomach strips and guinea-pig atria.

9 The data derived from our structure-activity study suggest that the minimum structure required for the full stimulation of NT receptors in these two preparations is H-Arg9-Pro10-Tyr11-Ile12-Leu13-OH. The sequence PyroGlu1-Leu2-Tyr3-Glu4-Asn5-Lys6-Pro7-Arg8- and the amino acids Ile12 and Leu13 appear to contribute mainly to the affinity or binding of NT to its receptor. The chemical groups responsible for the full activation (intrinsic activity) of NT receptors seem to be located in the sequence -Arg9-Pro10-Tyr11.

/pdf/the-stimulatory-effects-of-neurotensin-and-related-peptides-1ro0xjt97c.pdf

Serge St-Pierre

Papers

Autoradiographic distribution of [3H]neurotensin receptors in rat brain: visualization by tritium-sensitive film.

Characterization and visualization of cholecystokinin receptors in rat brain using [3H]pentagastrin.

The vasoconstrictor effect of neuropeptide Y and related peptides in the guinea pig isolated heart

Differential neurobehavioral effects of neurotensin and structural analogues.

The stimulatory effects of neurotensin and related peptides in rat stomach strips and guinea-pig atria.