Receptor potency

Meyers MJ, Sun J, Carlson KE, Marriner A, Katznellenbogen BS, Katzenellenbogen JA (2001) Estrogen receptor-/ potency-selective ligands structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 44 4230-4251... 

Hypertension Headaches due to increased blood pressure Switch to TCA with less NE receptor potency ... 

Dynorphinhas not been nearly as well studied as other smaller opioid peptides. Although several peptides with high affinity for k receptors are obtained from prodynorphin (see Section 3.4 above), SAR studies have focused on derivatives of dynorphin A (see Refs. 656, 753 for reviews). Dynorphin A is a heptadecapep-tide, but dynorphin A-(l-13) accounts for essentially all of the activity of the larger peptide (754). Further truncation of dynorphin A-(l-13) from the C-terminus identified the basic residues Arg and Lys as important for k receptor potency and selectivity (263). Thus, typically, dynorphin A-(l-13) or A-(l-l 1) has been used as the parent peptide for further modification. 

Isoetharine Is dispensed as a solution only for Inhalation administration to treat reversible bronchospasm of asthma. It has fallen Into relative disuse, because with high doses, there Is a significant Incidence of cardiovascular (pi-receptor) adverse effects and It has a low p2-receptor potency compared to newer p2-selectlve agonists. It has a 2- to 4-mlnute onset of action when Inhaled and a duration of action of 3 hours. Isoetharine has adverse effects similar to those of EPI, Including palpitations, tachycardia, nausea and vomiting, dizziness, tremor, and headache. Isoetharine may cause decreased levels of theophylline when coadministered. Cardiovascular effects are a concern when Isoetharine Is taken with other asthma drugs. 

Glucagon storage granules become unstable at high dilutions in the circulation, and the circulating hormone must exist mostly as monomers with little defined secondary structure. Receptor binding studies indicate hydro-phobic interactions between hormones and receptor. Work by Rodbell et al (1971) and Epand and Jones (1977) has shown that almost the entire molecule is required for full biological potency, since NH2-terminal or COOH-terminal modifications lead to decreased receptor potency, as does modi-... 

Table 12.3 The specificity of bis-trimethylammonium cations, of different chain-lengths, for two important acetylcholine receptors. (Potencies are relative 1.0 is maximal for each site)...

Several EA and dihydro-EA also exhibit agonistic activity on serotonin receptors. Potency of 4 and 8 as agonists of arterial 5-HT2A and 5-HTib/id is comparable to that of serotonin 105), and seems to be partially responsible for vasoconstrictive activity. In treatments of migraine, which is thought to be due to vasodilatation of carotid arteriovenous anastomoses, 4 and dihydroergotamine can affect ai- and a2-adrenergic receptors (106,107). 

Effect of 3-Substituent. The pyrrolecarboxylate confers much higher potency than any other 3-substituent examined. The pyridinecarboxylate ( ) is of very low activity. Hydrolysis to alcohol 6 destroys almost all receptor potency but retains much of the KD activity. 3-Deoxy- 0 and its acetate are reported to be insecticidal (20,21). Bromination or alkylation of the pyrrole to give 12 or 20 greatly reduces activity. It is not possible as yet to esterify at C-3 to examine other ester substituents. 

Effect of Alkylation. Alkylation at nitrogen or C-4 or conversion to di-, tri- or tetramethyl derivatives successively reduces activity (21-26 vs 1), in contrast to the enhanced receptor potency on methylation at C-10 converting 11 to IQ. 

---