Activator Replacement

No Less More Part of As well as Reverse Other tlian No part of intended function is accomplished Quantitative decrease in intended activity Quantitative increase in intended activity Tlie intention is acliieved to a certain percent Tlie intention is accomplished along with side effects Tlie opposite of the intention is achieved A different activity replaces tlie intended activity... 

Compound la with no substitution, showed good activity with increased hpophihcity activity. Further increases in lipophihcity led to a decrease in activity. Replacement of a proton of the methyl group by a hpophobic group (chloro) resulted in a further decrease in activity. The order of activity of substituents at the first position was methyl, ethyl, unsubstituted, propyl, and chloromethyl. Compounds with a small substituent at Ci seem to provide optimum activity. As the test compounds could not be converted to water soluble form, in vitro evaluation for antihistaminic activity could not be performed. 

To eliminate arylating activity, replace halogen ortho/para to the nitro group(s) to the meta position in nitroaromatic compounds. 

Substitution of oxygen in the Si—0—C system by the isoelectronic CH2 group leads to stable compounds with a decreased but prolonged antihistaminic, anticholinergic and antitremorine activity. Replacement of the oxygen atom by a NH group leads to compounds, showing no spasmolytic activity at all because of rapid hydrolysis of the Si—N bond. 

Finally, two synthetic peptide-type alkaloids may be briefly mentioned in this chapter since both show promising pharmacological activities. Replacing L-phenylalanine in the peptide part of ergotamine by a-methylalanine, a new peptide alkaloid (75) called 5 -methyl-ergoalanine was obtained in analogy to the synthesis of ergotamine... 

The other microarchitectural form of bone, lamellar bone, actively replaces maturing woven bone and, consequently, contains up to 100 times more mineralized matrix or hydroxyapatite these hydroxyapatite crystals... 

A series of 14 synthetic pyrroles, furans, thiophenes, and prolines were assayed using X. bifasciatum, the presence of bromine was important for activity, replacement of the pyrrolic N by either O or S did not affect activity, while the prolines tested were inactive.107 A later study compared the feeding deterrency of 65 and 66... 

Replacement of the o gen at C-2 by a sulfur atom results in faster onset but shorter duration of hypnotic activity. Replacement of more than one carbonyl o gen by sulfur causes a loss of activity, again indicating an upper limit to lipophilicity. 

Structure-Activity Relationships. Effects caused by initial structural modifications in the lead compound are shown in Table I. Replacement of the oxygen in 1 with sulfur caused complete loss of activity. Replacement of the phenyl moiety at the 2-position with benzyl, hydrogen, or alkyl gave inactive analogs ( -9 Similary, replacement of N-phenyl with hydrogen, alkyl,... 

Replacement of methionine by norleucine gave an analog with about 50% of the potency of the parent, but replacement of glycine or -OH led to marked loss of activity. Substitution of tyrosine by phenylalanine, blocking of the hydroxyl, or removal of the amino group practically abolished activity. Replacement of the Phe- by Tyr- also practically abolished acti-... 

The positively charged nitrogen atom is essential to activity. Replacing it with a neutral carbon atom eliminates activity. 

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