ABSTRACT
A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil.
Subject(s)
Adenosine/chemistry , Adenosine/pharmacology , Purinergic P1 Receptor Agonists , Adenosine/analogs & derivatives , Anti-Inflammatory Agents/chemistry , GTP-Binding Proteins , Solubility , Structure-Activity RelationshipABSTRACT
Incorporation of D-Pro9 into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-Trp9 by D-Pro9 in the nonselective neurokinin antagonist [Arg5,D-Trp7,9, Nle11]-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Pro10 provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 4; NK-2 pKB = 5.9; NK-1 pKB = 4.7; NK-3 pKB less than 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 pKB = 8.2), and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (compound 34, GR 94800; NK-2 pKB = 9.6; NK-1 pKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonist-induced bronchoconstriction in the anaesthetized guinea-pig.
Subject(s)
Neurokinin A/metabolism , Oligopeptides/pharmacology , Receptors, Neurotransmitter/antagonists & inhibitors , Amino Acid Sequence , Animals , Guinea Pigs , Male , Molecular Sequence Data , Oligopeptides/chemical synthesis , Receptors, Neurokinin-2 , Structure-Activity RelationshipSubject(s)
Neurokinin A/analogs & derivatives , Neurokinin A/antagonists & inhibitors , Neurokinin B/analogs & derivatives , Neurokinin B/antagonists & inhibitors , Substance P/analogs & derivatives , Substance P/antagonists & inhibitors , Amino Acid Sequence , Animals , Guinea Pigs , In Vitro Techniques , Intestinal Mucosa/metabolism , Intestines/drug effects , Intestines/physiology , Molecular Sequence Data , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Muscle, Smooth/physiology , Neurokinin A/chemical synthesis , Neurokinin A/pharmacology , Neurokinin B/chemical synthesis , Neurokinin B/pharmacology , Protein Conformation , Rats , Receptors, Neurokinin-1 , Receptors, Neurokinin-2 , Receptors, Neurokinin-3 , Receptors, Neurotransmitter/drug effects , Receptors, Neurotransmitter/metabolism , Structure-Activity Relationship , Substance P/chemical synthesis , Substance P/pharmacologyABSTRACT
With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.
