Selective bronchial relaxants and thromboxane antagonists
Duane Miller joined the faculty in the College of Pharmacy at The Ohio State University in 1969 and it was there that one of our earliest research projects was on making chemical changes on a molecule called trimetoquinol (TMQ) and to see how the modified analogs interacted with different beta ( ) receptors of the adrenergic nervous system. Norepinephrine is the neurotransmitter for this nervous system. Trimetoquinol (InolinR) is a drug used in Japan for bronchial relaxation in the treatment of asthma and emphysema and has some structural similarity to norepinephrine. Another professor, Dennis Feller ( at that time also at The Ohio State University and now at the University of Mississippi) was also interested in the fat breakdown ability of such drugs. We began a collaborative effort to see if modification of trimetoquinol could be made to improve the bronchial relaxant actions (adrenergic) relative to the cardiac stimulation ( 1 adrenergic) and fat breakdown properties. We synthesized and developed 8-fluoro-trimetoquinol (8F-TMQ) which was patented at The Ohio State University as a selective bronchial relaxant.
In 1992 our family moved to Memphis and I joined the faculty in the College of Pharmacy at University of Tennessee. We have recently found some of our newly synthesized analogs like 3 ,5 -diiodotrimetoquinol (3 ,5 -diiodo TMQ) to be selective for the breakdown of fat ( 3 adrenergic) and we have submitted a new set of drugs for patents. We are working on a hypothesis that trimetoquinol binds to a least three areas on the adrenergic receptors including a catechol, amino and trimethoxybenzyl sites. Currently we are using molecular modeling to help us define how drugs bind to the different adrenergic receptors.
Trimetoquinol (TMQ) is a novel tetrahydroisoquinoline drug which interacts stereoselectively with á-adrenergic (á1-, á2- and á3- subtypes) and thromboxane A2 (TXA2) [alpha- and tau- subtypes] receptors.1 Our hypothesis is that TMQ binds in a three-point attachment to both of these receptor systems, and interactions with receptor domains include the catechol, amino and trimethoxybenzyl moieties. For the á-adrenoceptor, we believe that TMQ binds with serines (Ser) 204 and 207 (catechol group), aspartic acid (Asp) 113 (amino group), and a third unknown region (trimethoxybenzyl group).
The primary objective of this proposal is to synthesize and study highly selective photoaffinity and affinity labels of TMQ as probes of TXA2 and á-adrenergic receptors, and to utilize mutant á-adrenoceptor systems for defining specific receptor binding domains. Because of the major differences in optical isomers of TMQ analogs (TMQ and 8-fluoro TMQ) and high potency of the 3 -iodo and 3 ,5 -diiodo TMQ on TXA2 and á-adrenergic receptors, we have designed optically active radiolabeled photoaffinity and affinity labels for probing these two distinct receptor systems. A second part of the proposal will be to synthesize a series of catechol mimetic analogs of TMQ that will investigate the importance of hydrogen bonding to receptors, and should provide more selective (á2 versus á1) and longer-acting [resistant to Catechol O-Methyl Transferase (COMT) metabolism] drugs than the parent molecule as á- agonists (bronchial relaxants) and TXA2 antagonists (antiaggregatory and hypotensive activities).
Affinity compounds will be used for biochemical characterization of molecular mass and isoelectric points of drug bound receptor proteins, and of peptide mapping and amino acid sequencing of relevant peptides. We will also examine ligand binding domains for TMQ analogs using mutant á-adrenoceptors, and define relationships between receptor occupancy and signal transduction for TMQ analogs using cells expressing unmutated á-adrenoceptors. Newly synthesized drugs will be evaluated for receptor specific interactions in á-adrenergic (á1-, á2- and á3-) and TXA2 (smooth muscle and endothelial cells, platelets) tissues.
The main purpose is to characterize specific receptor site interactions of tetrahydroisoquinolines with á-adrenergic and TXA2-receptor systems. Our long-term goal is to separate the desired bronchial dilation from the undesired á2-adrenergic effects on skeletal muscle (tremors) and to differentiate between the platelet aggregatory and vasoconstrictive effects of TXA2 and to develop selective. We also are very interested in developing selective á3-adrenergic agonists for the breakdown of fat.